DEFINITION OF METABOLIC SYNDROME

Metabolic syndrome is characterized by the presence of a constellation of abnormalities that include abdominal obesity, dyslipidemia, hypertension, insulin resistance, microalbuminuria, and prothrombotic and pro-inflammatory states. These abnormalities result in an increased risk of atherosclerotic cardiovascular disease (CVD) and diabetes mellitus.

Metabolic syndrome is widespread throughout the world, and its prevalence is expected to increase dramatically in the coming years.^1-7 The rate of its occurrence is growing exponentially, especially in children and young adults.^6,8

The table below describes the 3 sets of criteria commonly used to define the presence of metabolic syndrome. The most recent of these, released by the International Diabetes Foundation (IDF), includes sex- and ethnic group–specific elevated waist circumference as a major criterion in its definition of metabolic syndrome.

World Health Organization definition (modified version)

• Fasting plasma glucose level greater than 100 mg/dL (6.1 mmol/L)
• Hyperinsulinemia (upper quartile of fasting insulin in nondiabetic population)
• Diabetes or impaired glucose tolerance

• Presence of hyperlipidemia (defined as serum triglyceride level ≥150 mg/dL [1.7 mmol/L])
• Low-density lipoprotein (LDL) cholesterol level greater than 150 mg/dL (1.7 mmol/L) or serum high-density lipoprotein (HDL) cholesterol level less than 35 mg/dL (0.9 mmol/L)
• Blood pressure greater than 140 mm Hg systolic or 90 mm Hg diastolic or patient taking medication to lower blood pressure
• Obesity (waist-to-hip ratio >0.9 or body mass index [BMI] >30 kg/m2)

National Cholesterol Education Program definition

The National Cholesterol Education Program (NCEP) defines metabolic syndrome according to a single list of criteria. A patient must meet at least 3 of the following criteria:

• Fasting plasma glucose level greater than 110 mg/dL (6.1 mmol/L)
• Serum triglyceride level greater than 150 mg/dL (1.7 mmol/L)
• Serum HDL cholesterol level less than 40 mg/dL (1.04 mmol/L) in men or less than 50 mg/dL (1.29 mmol/L) in women
• Blood pressure higher than 130 mm Hg systolic or 85 mm Hg diastolic or patient taking medication to lower blood pressure
• Abdominal obesity (waist girth >102 cm for men or >88 cm for women)

International Diabetes Foundation definition

Like the WHO, the IDF consults 2 different categories of conditions to define metabolic syndrome. To diagnose metabolic syndrome based on the IDF definition, a patient must be obese (as determined by sex- and ethnic group–specific elevated waist circumference) and also have at least 2 of the following conditions:

• Fasting plasma glucose level greater than 100 mg/dL (5.6 mmol/L) or previously diagnosed type 2 diabetes mellitus
• Serum triglyceride level greater than 150 mg/dL (1.7 mmol/L) or patient taking specific treatment
• Serum HDL cholesterol level less than 40 mg/dL (1.04 mmol/L) in men or less than 50 mg/dL (1.29 mmol/L) in women or patient taking specific treatment
• Blood pressure greater than 130 mm Hg systolic or 85 mm Hg diastolic or taking medication to lower blood pressure

• Women of European descent - Greater than 80 cm
• Men of European descent - Greater than 94 cm
• Women of South Asian (Chinese and Japanese) descent - Greater than 80 cm
• Men of South Asian (Chinese and Japanese) descent - Greater than 90 cm
• Women and men of South and Central American descent - Same as South Asian cutoffs until more specific data are available
• Women and men of eastern Mediterranean, Middle Eastern, and sub-Saharan African descent - Same as European cutoffs until more specific data are available

PATHOPHYSIOLOGY

The underlying cause for metabolic syndrome is unclear. However, it may be related to central obesity, insulin resistance, dyslipidemia, and hypertension, all of which stem from dietary excess, a sedentary lifestyle, and genetic predisposition. Further research is required to pinpoint the exact etiology of this syndrome.

EVIDENCE LINKING METABOLIC SYNDROME AND CARDIOVASCULAR DISEASE

Since the release of the NCEP guidelines for metabolic syndrome in 2001, numerous published clinical studies have established that people with metabolic syndrome are twice as likely to develop CVD and are at an overall increased risk of mortality.^4,5,9-15 The most recent of these studies, which involved a large community-based sample of middle-aged men, demonstrated that, after taking established cardiac risk factors into account, people with metabolic syndrome were at a 40-60% increased risk for total and cardiovascular mortality.¹⁶

The increased risk was found across all age groups, including young adults and adolescents. Most of the studies published in early 2000 focused on middle-aged adults. However, a recently published study proved that even young adults have higher cardiovascular risks if they have metabolic syndrome.¹⁷ The researchers found that the carotid intimal-medial thickness (CIMT), a marker of subclinical atherosclerosis and future cardiovascular events, was increased in young adults with metabolic syndrome. The composite CIMT increased in tandem with the number of metabolic syndrome components present in a patient.

A study published by McNeill and colleagues on a large population-based cohort involving elderly adults with a mean age of 72 years revealed that older adults with metabolic syndrome are also at increased risk.¹⁸ This study proved the link between metabolic syndrome and the development of CVD. In another study, patients aged 70-79 years were observed for 6 years.¹⁹ The results of that study showed that metabolic syndrome was associated with an increased coronary and cardiovascular mortality.

Another interesting observation obtained from a recently published study is that metabolic syndrome confers a higher long-term risk of death in patients with preexisting coronary heart disease (CHD).²⁰ Dysglycemia appears to be responsible for most of the associated risk.

CONTROVERSY

Whether metabolic syndrome criteria enhance prediction of CVD events beyond the Framingham Heart Study prediction score is still controversial. As metabolic syndrome criteria do not include major, well-established cardiovascular risk factors such as age, smoking, and LDL cholesterol levels, metabolic syndrome criteria are considered inferior to the Framingham score in predicting CVD events.^21,22

However, among individuals with the same Framingham score, those with metabolic syndrome are at higher risk of CHD than are those without metabolic syndrome. Also, a clear gradation in the risk of CHD outcome is evident with each additional component of metabolic syndrome; men with 3 or more components and women with 2 or more components are at statistically elevated risk.²²

The Framingham Heart Study prediction score can be used for short-term (<10 y) prediction of CHD events, whereas metabolic syndrome criteria can be used to predict events in the long term.²³ However, the utility of metabolic syndrome criteria as predictive of CHD events is questionable and needs to be well defined.²⁴

TREATMENT

Whether treatment specific to the components of metabolic syndrome results in better outcomes is currently unknown. Lifestyle modifications such as weight loss, aerobic exercise, smoking cessation, and improved diet independently improve insulin resistance and slow progression to type 2 diabetes mellitus. Even though success achieved through lifestyle modification is limited, the significance of it cannot be overemphasized.

Pharmacotherapy involves the aggressive management of well-established risk factors (eg, hypertension, obesity, dyslipidemia).

WHERE DO WE GO FROM HERE?

The definition of metabolic syndrome must be refined to better predict the occurrence of future cardiovascular events. The definitions provided by the WHO, NCEP, and IDF combine traditional risk factors and components of metabolic syndrome. Additional research is needed to determine whether treatment of underlying causes for metabolic syndrome (eg, insulin resistance) results in better outcome beyond the levels achieved by interventions that target conventional cardiovascular risk factors. Until then, treatment should be aimed at well-established risk factors.

REFERENCES

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21. Sattar N. The metabolic syndrome: should current criteria influence clinical practice? Curr Opin Lipidol. Aug 2006;17(4):404-11.

22. McNeill AM, Rosamond WD, Girman CJ, et al. The metabolic syndrome and 11-year risk of incident cardiovascular disease in the atherosclerosis risk in communities study. Diabetes Care.2005;28(2):385-90.

23. Grundy SM. Does the metabolic syndrome exist? Diabetes Care. 2006;29(7):1689-92; discussion 1693-6.

24. Kahn R. The metabolic syndrome (emperor) wears no clothes. Diabetes Care. 2006;29(7):1693-6.