Author: Dr Elena Citkowitz Yale University 2009-01-24
The Metabolic Syndrome (Syndrome X, insulin resistance syndrome) :
The metabolic syndrome is made up of a constellation of abnormalities that increase the risk for developing diabetes and possibly for coronary artery disease.
Overview
- Why is the metabolic syndrome important?
- What is the metabolic syndrome?
- Recent definitions of the metabolic syndrome
- Controversies about the metabolic syndrome
- Causes of metabolic syndrome
- Diagnosis of metabolic syndrome
- Treatment of metabolic syndrome
- Links, references
Why is the Metabolic Syndrome Important?
Many
studies have shown that the metabolic syndrome increases the risk for
developing cardiovascular disease (CVD) (heart attack and stroke) and
type 2 diabetes (formerly called adult onset diabetes). But controversy exists on many levels: Does
the constellation of metabolic abnormalities that constitute the
metabolic syndrome provide any more predictive value than does the risk
entailed by each component separately? If the concept of the metabolic syndrome is productive, what is the best definition? As
the definition includes some measure of obesity, how is that condition
best determined? If waist circumference is thought to be the best
measure of obesity, what values should be applied to different ethnic
groups? If ethnic-appropriate values are agreed upon, what is the best method for measuring waist circumference? Unfortunately no definitive answers have been arrived at for any of the above concerns. Nevertheless,
many experts believe the metabolic syndrome contributes substantially
to our understanding of why CVD and DM develop and many studies continue
to show their strong association with the metabolic syndrome. Some
studies show that having the metabolic syndrome increases the risk for
developing diabetes but not cardiovascular disease.
What is the Metabolic Syndrome?
The metabolic syndrome is a grouping of several clinical conditions that together increase. Use of the term ‘syndrome’ does not imply a single disease entity as do the terms Down’s syndrome and Tourette’s syndrome. The
metabolic syndrome is not a single disease entity and, as will be
discussed below, some experts do not think that the metabolic syndrome
adds anything to patient care and that this grouping of multiple medical
conditions is no more predictive than considering each condition
independently.
While
the metabolic syndrome has been increasingly the focus of discussion in
medical journals and public forums, the concept is hardly new. It
began with the recognition that insulin resistance (see below) is
accompanied by many other metabolic abnormalities. Insulin is a hormone
produced by the pancreas that controls blood glucose (sugar) levels by
moving it into cells where it can be used for energy or stored. Insulin resistance is a condition in which cells do not take up glucose efficiently because they are less sensitive to insulin. When
insulin resistance first develops, the blood glucose (sugar) level is
usually normal because the pancreas can produce more insulin to
compensate for the resistance so that blood glucose is still absorbed.
Insulin resistance is the precursor of type 2 diabetes, the so-called
“adult onset” diabetes. As insulin resistance increases,
greater insulin production is required to keep blood sugar down to
normal levels. When the pancreas is no longer able to maintain normal or
near-normal levels of blood glucose, diabetes develops.
In
1988, Gerald Reaven linked the insulin resistance syndrome to a cluster
of conditions: elevated blood glucose, elevated blood pressure,
elevated triglycerides, and low high-density lipoprotein (HDL)
cholesterol. He concluded that this “cluster of related
abnormalities” increases the risk for atherosclerotic cardiovascular
disease (ASCVD), hardening of the arteries, particularly arteries
supplying the heart and brain. He called it syndrome X,
which is not to be confused with a completely different ‘syndrome X’
that refers to a cardiac condition involving spasm of the coronary
arteries. Reaven’s formulation was so widely accepted that it soon became know as Reaven’s syndrome.
Announcement for Reaven’s National Institutes of Health Astute Clinician Lecture November 3, 2004
As
originally described, syndrome X/Reaven’s syndrome is not synonymous
with the current definitions of metabolic syndrome, but the underlying
concepts are the same.
Defining the Metabolic Syndrome
Many
organizations have stated their requirements for the diagnosis of the
metabolic syndrome and differences abound but conditions Reaven noted in
his original formulation are common to all.
- A test reflecting the presence of insulin resistance
- Elevated blood pressure
- Elevated triglyceride levels (a blood fat)
- Low HDL cholesterol (the good cholesterol)
- A measurement reflecting the presence of central obesity, with the exception of BMI in the WHO criteria (see below)
1998-1999 Definitions of and Criteria for the Metabolic Syndrome
The
World Health Organization definition (WHO) (1998) and its modification
by European Group for the Study of Insulin Resistance (EGIR) (1999)
retained Reaven’s original focus on insulin resistance. In
addition to two other risk factors for the metabolic syndrome: some
evidence of insulin resistance was an absolute requirement. The WHO
criteria differed from all subsequent definitions in two respects: 1) one of the risk factors was a measure of renal (kidney) impairment based on the amount of protein excreted in the urine. 2) In the 1998 definition, obesity was determined either by waist-to-hip ratio or body mass index (BMI). The EGSIR used the term insulin resistance syndrome rather than the metabolic syndrome. Waist circumference was substituted for waist-to-hip ratio and dropped BMI, and urinary protein was eliminated. The
update retained the requirement for evidence of insulin resistance but
stipulated that a high plasma insulin level be present. Among
the two additional risk factors required to meet the criteria, the EGIR
allowed fasting blood glucose but not type 2 diabetes (DM-2), formerly
called adult-onset diabetes.
2001-2003 Definitions of and Criteria for the Metabolic Syndrome
In
2001, led by Dr. Scott Grundy, the National Cholesterol Education
Program Adult Treatment Panel (ATP III) was published and became what is
now probably the most widely used definition of the metabolic syndrome
in the United States. Neither the insulin resistance syndrome nor any other single condition was a necessary component. The
risk factor used as a surrogate for insulin resistance could be either
DM-2 or an impaired fasting plasma glucose level (IFG).
Scott Grundy, MD
The 2003 position statement by the American College of Endocrinology reasserted the primacy of insulin resistance and dropped the term ‘the metabolic syndrome’. As in the earliest guidelines, insulin resistance was made a necessary component syndrome. A specific number of other risk factors was not mandated; and although DM-2 could not be used in making the diagnosis, several clinical scenarios not included in other guidelines were added: family history of DM-2, ethic groups prone to DM, sedentary lifestyle, advancing age, and polycystic ovary syndrome (a condition often accompanied by insulin resistance and its associated abnormalities).
Recent Definitions of and Criteria for the Metabolic Syndrome
The
usefulness of the metabolic syndrome lies in its ability to predict an
individual’s risk of developing CAD or diabetes; and in this respect,
the WHO, EGIR, and ATP III definitions are not accurate when applied all
ethnic groups, because diabetes risk increases in Asians and others
with smaller degrees of central obesity.
To
address this problem and in the hope of developing a tool that could be
used internationally, the International Diabetes Federation (IDF), a
group with worldwide representation, developed a new classification. The IDF made two major changes in the ATP III definition for the metabolic syndrome. They
concluded that both insulin resistance and central obesity are
“important causative factors”. Abdominal obesity was made a prerequisite
for the diagnosis of the metabolic syndrome, acknowledging that
measuring insulin resistance is impractical in daily practice. The
four other ATP III criteria were adopted unchanged with the exception
of a more stringent definition for impaired fasting glucose that had
been accepted since its publication: (fasting plasma glucose 100 mg/dL (5.6 mmol/L) or higher) (Table 1).
Table 1: The new International Diabetes Federation (IDF) definition
According to the new IDF definition, for a person to be defined as having the metabolic syndrome they must have:
Central obesity (defined as waist circumference > 94cm for Europid men and > 80cm for Europid women, with ethnicity specific values for other groups)
plus any two of the following four factors:
- raised triglyceride level: > 150 mg/dL (1.7 mmol/L), or specific treatment for this lipid abnormality
- reduced HDL cholesterol: < 40 mg/dL (1.0 mmol/L) in males and < 50 mg/dL (1.3 mmol/L) in females, or specific treatment for this lipid abnormality
- raised blood pressure: systolic BP > 130 or diastolic BP > 85 mm Hg, or treatment of previously diagnosed hypertension
- raised fasting plasma glucose (FPG) > 100 mg/dL (5.6 mmol/L), or previously diagnosed type 2 diabetes
The
IDF also delineated multiple, ethnic specific values for waist
circumference and defined more stringent criteria for whites of European
descent.
Europids:
the cut point for abnormal waist circumference decreased from 102 cm
(40 inches) to 94 (37 inches) in men and from 88 cm (35 inches) to 80
(31.5 inches) for women. The IDF conceded that in the USA, the ATP III values (male 102 cm, female 88 cm) are likely to continue to be used.
Chinese and South Asians (based on Chinese, Malay, and Asian-Indian populations):
male > 90 cm, female > 80 cm
Japanese: male > 85 cm, female > 90 cm
Until
more specific data are available, the IDF recommended that South Asian
recommendations be used for Ethnic South and Central Americans and
European data be applied to Sub-Saharan Africans and Eastern
Mediterranean and Middle East (Arab) populations.
The IDF also stated that further investigation is necessary to validate abnormal waist circumference for various ethnic groups. The IDF also provided recommendations for treatment of the conditions making up the m
etabolic syndrome.
etabolic syndrome.
Later
in 2005, with Grundy as lead author, the American Heart Association and
National Heart, Lung, and Blood Institute published a statement on the
diagnosis and management of the metabolic syndrome that modified the ATP
III definition. Among other changes, it used the lower
value for an abnormal fasting blood glucose (FBG) and noted that a lower
cut point for waist circumference should be applied to Asians. Lifestyle interventions were also discussed and their importance in risk reduction emphasized.
2005 ATP III/AHA, NHLBI Diagnostic Criteria for the Metabolic Syndrome
Any 3 of the following 5 conditions fulfill the definition of the metabolic syndrome (using abnormal FBG as currently defined):
- Fasting blood glucose 100 mg/dL (5.6 mM) or more or
Drug treatment for elevated FBG
- Waist Men: 40 inches (102 cm) or more; Women:35 inches (88 cm) or more
- Blood pressure Systolic: 130 mm Hg or more or
Drug treatment for hypertension
- HDL Men: below 40 mg/dL (1.03 mM); Women:below 50 mg/dL (1.3 mM) or
Drug treatment to raise HDL
- Triglycerides 150 mg/dL (1.7 mM) or
In 2005, the American College of Endocrinology (ACE) and the American Association of Clinical Endocrinologists published a statement reaffirming the ACE’s 2003 position statement on the insulin resistance syndrome, and agreeing with other organizations’ recent definitions and updates of the metabolic syndrome.
( http://www.aace.com/pub/pdf/guidelines/IRSStatement.pdf )
mentioned by one or more of the above statements and by other
authorities as warranting further study for possible inclusion in later
definitions: Measures of inflammation and coagulation, abnormalities in
blood vessel and sympathetic nervous system function, and elevated uric
acid metabolism are among the most commonly mentioned.
Based
on the ATP and IDF definitions of the metabolic syndrome, gender and
age-specific criteria have also been developed for adolescents aged
12-19.
Controversies about the Metabolic Syndrome
As
the above discussion illustrates, a single definition for the metabolic
syndrome has not been universally accepted, in part because of
uncertainties about ethnic-appropriate definitions for at-risk waist
circumference but also because of concerns with the very concept of the
metabolic syndrome. In 2005, a Joint Statement from the American Diabetes Association and the European Association for the Study of Diabetes raised many of these concerns (Table 3).
Table 3
Summary of concerns regarding the metabolic syndrome
1) Criteria are ambiguous or incomplete. Rationale for thresholds are ill defined. 2) Value of including diabetes in the definition is questionable.
3) Insulin resistance as the unifying etiology is uncertain.
4) No clear basis for including/excluding other CVD risk factors.
5) CVD risk value is variable and dependent on the specific risk factors present.
6) The CVD risk associated with the “syndrome” appears to be no greater than the sum of its parts.
7) Treatment of the syndrome is no different than the treatment for each of its components.
8) The medical value of diagnosing the syndrome is unclear.
Each of these concerns requires extensive discussion beyond the scope of this article but one issue may neutralize all of them: One
of the most compelling arguments for retaining the concept of the
metabolic syndrome is that it provides clinicians (at least in the
United States current ‘managed care’ environment) with an approved
diagnostic code for the metabolic syndrome (277.7 approved in 2001) that
allows them to be reimbursed for the diagnosis and treatment of one or
more components of the syndrome. For example, treating a mildly elevated
blood pressure that is not high enough to qualify for the diagnosis of
hypertension will not be reimbursed by Medicare and many other
healthcare plans. But if the elevated blood pressure is
accompanied by two (or more) other components of the metabolic syndrome,
a situation that commonly occurs, then time spent counseling patients
and doing appropriate diagnostic tests will be reimbursed. Take
away the metabolic syndrome and interventions that have been proven to
prevent or delay the development of outright hypertension and diabetes
may not be addressed.
Another argument favoring acceptance of the syndrome is the emphasis it brings to treatment of patients CVD or diabetes. Because
the metabolic syndrome increases the risk for a CVD event, a report was
issued in 2004 by the National Cholesterol Education Program report, in
which the recommended LDL goal of less than 100 mg/dL (2.6 mM) could be
lowered to less than 70 mg/dL (1.8 mM) if these patients had the
metabolic syndrome.
Causes of the Metabolic Syndrome
Insulin resistance
Insulin
resistance and the metabolic syndrome appear to be almost inseparable.
Insulin resistance was the basis of Reaven’s ‘syndrome X’; and several
organizations’ definitions of the metabolic syndrome required presence
of insulin resistance, which cannot be said of any other criterion. But other organizations make no such restriction. An
elevated fasting blood glucose (used by some as a surrogate for insulin
resistance) is one of 5 components of the ATP III/AHA, NHLBI definition
but any 3 conditions may be present for the diagnosis.
What
about the abdominal obesity (also called central, visceral,
male-pattern, android or apple-shaped obesity) which all organizations,
other that the WHO, require for the obesity component of the definition? Fat
deposition in the upper body, and particularly intra-abdominal fat
(visceral adiposity), has been thought to have greater metabolic
consequences than fat on the hips or thighs, which is more common in
women. Visceral adiposity is approximately 20% and 6% of
total body fat in men and women, respectively. Unlike subcutaneous fat,
blood circulation from visceral fat flows directly into the liver,
thereby exposing it to high concentrations of free fatty acids and other
chemicals and causing increased production of triglycerides and
increased insulin resistance.
That
being said, the vast majority of those with the metabolic syndrome are
overweight or obese; and one of the more straight-forward examples of
how great an impact this condition has on the other components of the
syndrome is their resolution following weight reduction surgery (gastric
bypass or gastric banding). Diabetes, high blood pressure, high triglycerides and low HDL can dramatically improve with major weight loss. And it must be said that obesity leads to – insulin resistance. Obesity
is increasing at an alarming rate in U.S. (see Figures) and much of the
industrialized world (see Figures) and, as a consequence, the metabolic
syndrome is also.
At this point, the discussion becomes increasingly “circular”. Sedentary
lifestyle, that is, the lack of aerobic exercise is a major factor in
the metabolic syndrome. But lack of exercise also tends to increase
weight, FBG, insulin resistance, blood pressure, and triglycerides. With sufficient daily physical activity, the metabolic syndrome would disappear.
A
diet high in refined carbohydrates (sweets, regular soda, juice, white
flour, white potatoes) at least indirectly promotes the metabolic
syndrome in that it leads to weight gain, increased triglycerides, and a
low HDL. Such diets are often high in sodium (salt), which increases the risk of high blood pressure.
Aging
increases the incidence of high blood pressure and elevated blood
glucose; and older individuals tend to be less physically active (which
leads to higher blood pressure and blood glucose).
Family history (parents or siblings) of DM-2
Polycystic ovary syndrome (a condition in which ovaries have multiple cysts.)
Diagnosis of the Metabolic Syndrome (any 3 of the 5 listed conditions)
The definitions and criteria discussed earlier provide the parameters for the diagnosis of the syndrome:
- Fasting blood glucose (FBG)
- Fasting triglycerides
- HDL cholesterol
- Blood pressure, measured by a clinician
- Waist circumference, measured by a clinician
The
first three components of the metabolic syndrome require a fasting
blood test for both the glucose and triglyceride levels; that is,
nothing should be eaten or drunk other than water for 10 to 12 hours
preceding the test. Ideally, exercise should also be avoided.
How is waist circumference measured?
AHA,NHLBI
recommendation for waist measurement is quite precise: place a tape
measure at the top of the right iliac crest (pelvis), circle the abdomen
on a horizontal plane parallel to the floor, make the tape snug without
compressing the skin, and measure at the end of a normal expiration.
Other methods: measurement at the umbilicus; where the waist is narrowest; and half-way between the last rib and the iliac crest; narrowest point between the costal (rib) margin and iliac crest.
Why isn’t body mass index (BMI) used instead of waist circumference?
The
definition of the metabolic syndrome uses waist circumference as a
surrogate for central obesity and body mass index (BMI), a ratio of
weight to height (weight in kilograms divided by height in meters
squared), provides no indication of the location of fat deposits or
even, for that matter, whether a high BMI indicates too much fat. BMI is used to define different categories weight (link to BMI calculator: http://www.nhlbisupport.com/bmi/)
Body Mass Index Categories
- Underweight: below 18.5
- Desirable weight: 18.5-24.9
- Overweight: 25-29.5
- Obese: 30-39.5
- Severely obese: 40 or higher
While
these cutpoints are reasonably accurate when applied to most
individuals in the U.S., it should be apparent that in some
circumstances the height-weight ratios categories of overweight and
obese reflect great than normal muscle mass, not fat (e.g. a body
builder who develops a very large muscle mass). Those with a BMI in the obese range may not have visceral obesity, and those with visceral obesity may have a BMI less than 30.
Waist measurement indicates both too much fat and its central location. The
waist-to-hip ratio, which was the WHO criterion for visceral obesity,
is another measure of the same condition: normal in women: less than
0.8; in men: less than 1.0. Hip measurement is less controversial than that of waist and is usually measured at the maximum circumference above the buttocks. Waist-to-hip ratio has been shown to more accurately predict heart attacks than BMI.
Central
obesity is most accurately determined by imaging techniques such as
direct measurement of visceral fat by computer assisted tomography or
magnetic resonance imaging, which are expensive and impractical in
clinical research and office settings.
Though central or upper body obesity probably poses a greater risk for CVD and DM-2, obesity (defined as a BMI of 30 or greater), whatever the distribution of fat, is also associated with a significant risk. With all its faults (confounding factors of muscle mass or bone mass), the BMI remains a useful concept.
Treatment for the Metabolic Syndrome
No specific treatment is recommended for the metabolic syndrome other than changes in lifestyle. The
ATP III cholesterol guidelines specifically incorporated the definition
of the metabolic syndrome in order to increase the likelihood that
lifestyle changes would be promoted by clinicians caring for individuals
not only with diabetes and high blood pressure but also for those with
mild increases that are now called prediabetes (fasting blood glucose
100 -125 mg/dL) and prehypertension (systolic blood pressure 130-139 or
diastolic blood pressure (80-89).
Lifestyle
As
the most frequent causes of the metabolic syndrome stem from obesity,
sedentary and poor diet, all the features of the metabolic syndrome will
improve with if one aspect of lifestyle intervention.
- Weight
Weight loss or more specifically decrease the percent body fat. Weight loss improves insulin sensitivity, increases HDL cholesterol and decreases FBG, blood pressure and triglycerides.
- Exercise
Frequent aerobic exercise will improve the same parameters as losing body fat. The
current suggested minimum regimen is at least 30 minutes of brisk
aerobic exercise (e.g. brisk walking) 4 days/week plus a modest amount
of strength training. The optimal amount of aerobic exercise is 60
minutes 7 days/week.
- Diet
- Fat
Total fat 25-35% of total calories.
Low fat diets increase triglycerides and lower HDL
Low fat diets increase triglycerides and lower HDL
- Carbohydrates
Add whole grains, fruit, vegetables
- Protein
- Reduce alcohol
- Because the metabolic syndrome increases the risk of a CVD event, other risk factors for that condition should be addressed:
- Smoking cessation
- Treatment of elevated LDL cholesterol
- Treatment for DM
- Treatment for high blood pressure
Medication
No
medication has been approved by the U.S. Food and Drug Administration
(FDA) for the specific indication of treating the metabolic syndrome. Nevertheless,
if a patient with the metabolic syndrome has an elevated FBG, many
experts will use metformin, a medication that is approved for the
treatment of DM-2 and which has been shown to reduce the risk of
developing diabetes in those with mildly elevated FBG. That
study of overweight, sedentary women showed that metformin reduces the
likelihood of developing diabetes but that intensive lifestyle changes
were even more effective. An important trial cosponsored by the U.S.
National Institutes of Health (NIH) is evaluating whether combining a
medication to raise HDL and lower triglycerides (extended-release
niacin) with a statin to aggressively lower the LDL, will improve
clinical outcomes in high-risk patients with the metabolic syndrome.
The study, Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides and Impact on Global Health Outcomes (AIM-HIGH), is enrolling more than 3,000 patients. Results are not expected until 2011.
Circumstances in which medication is indicated
- Treatment of hypertension (high blood pressure)
First-line
therapy for patients with the metabolic syndrome is either angiotensin
converting enzyme inhibitors or angiotensin-receptor blockers, which do
not increase FBG or triglycerides or decrease HDL cholesterol.
- Treatment of diabetes
Drugs
of choice are metformin, which decreases the glucose output by the
liver and also increases insulin sensitivity; and a group of drugs
called TZDs (thiazolidinediones), which improve insulin sensitivity.
- For significantly elevated triglycerides
- Fibrates (gemfibrozil, fenofibrate, bezafibrate, clofibrate) lower triglycerides and increase HDL cholesterol
- Niacin at doses of at least 1000 mg lowers triglycerides, raises HDL cholesterol, and also lowers low-density lipoprotein (LDL), the ‘bad’ cholesterol. Niacin sometimes increases FBG but is contraindicated neither in DM-2 or the metabolic syndrome.
- High dose fish oil
- For HDL cholesterol below 40 mg/dL. In patients with atherosclerotic disease or diabetes, the ATP III guidelines suggest using either niacin or a fibrate (gemfibrozil, fenofibrate, bezafibrate, clofibrate) to raise the HDL cholesterol.
Links
American Heart Association: What is atherosclerosis?http://www.nhlbi.nih.gov/health/dci/Diseases/Atherosclerosis/Atherosclerosis_WhatIs.html
Centers for Disease Control and Prevention (CDC)
Physical activity
http://www.cdc.gov/nccdphp/dnpa/physical/index.htm
Centers for Disease Control and Prevention (CDC)
Information on overweight and obesity, BMI calculator (adults and children/teens), physical activity, nutrition
http://www.cdc.gov/nccdphp/dnpa/obesity/trend/maps/
American Heart Association: Why Lose Weight?
http://www.americanheart.org/presenter.jhtml?identifier=3040449
Physical
Activity and Public Health. Updated Recommendation for Adults from the
American College of Sports Medicine and American Heart Association. Haskell WL, et al. Circulation 2007;116:1081-1093.
Physical
Activity and Public Health. Updated Recommendation for Older Adults
from the American College of Sports Medicine and American Heart
Association.
Nelson ME, et al. Circulation 2007;116:1094-1105.
References
Definitions
1.
World Health Organization: Definition, Diagnosis, and Classification of
Diabetes Mellitus and its Complications: Report of a WHO Consultation.
Geneva, World Health Org, 1999.
2. Executive
Summary of the Third Report of the National Cholesterol Education
Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of
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the American Diabetes Association and the European Association for the
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7. Grundy SM, Cleeman JI, Daniels SR, et al. Diagnosis and Management of the Metabolic Syndrome. An American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Circulation 2005;112:2735-2752. http://circ.ahajournals.org/cgi/reprint/112/17/e285
8. American
College of Endocrinology/American Association of Clinical
Endocrinologists: Reaffirmation of the 2003 ACE Insulin Resistance
Syndrome (IRS) Position Statement. 2005.
9. Grundy SM. (A state of the art paper) Metabolic syndrome: connecting and reconciling cardiovascular and diabetes worlds. J Am Coll Cardiol 2006;47:1093-1100Other
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