Sci. Aging Knowl. Environ., 28 June 2006
Vol. 2006, Issue 10, p. pe19
[DOI: 10.1126/sageke.2006.10.pe19]

PERSPECTIVES

A Work in Progress: The Metabolic Syndrome

Jose A. Luchsinger

The author is in the Department of Medicine at Columbia University, New York, NY 10032, USA. E-mail: jal94{at}columbia.edu

http://sageke.sciencemag.org/cgi/content/full/2006/10/pe19

Key Words: metabolic syndrome • insulin resistance • vascular risk factors • cardiovascular disease • lifestyle changes

Introduction

Scientists have recognized for some time that traditional cardiovascular risk factors, which include diabetes, dyslipidemia (altered levels of lipoproteins and triglycerides), and hypertension, usually occur together in individuals. One of the first names for this phenomenon was "metabolic syndrome X," a term coined by Reaven (1); it is also referred to as insulin resistance syndrome. At first, scientists thought that resistance to insulin, caused in part by central obesity (2), was responsible for the clustering of these risk factors, but the causes may be more heterogenous (3) (see Hornsby Review, Block Perspective, and "Mucking With Metabolism").

More recently, researchers have been referring to metabolic syndrome X simply as "the metabolic syndrome" (3). The name denotes the clustering of dyslipidemia, hypertension, and elevated plasma glucose, as well as abdominal obesity (see "Greasing Aging's Downward Slide"). Dyslipidemia occurs in the form of high cholesterol, high triglycerides, or low high-density lipoprotein (HDL). The latter two abnormalities, however, can occur even when cholesterol levels are close to normal. Each risk factor individually increases the risk of future cardiovascular disease. When risk factors occur in a cluster, they may increase the risk of cardiovascular disease even further and predispose individuals to the development of diabetes.

One study estimated the prevalence of metabolic syndrome in middle-aged adults without diabetes or cardiovascular disease to be 26.8% in men and 16.6% in women (4). These individuals have a twofold increase in the risk of atherosclerotic cardiovascular disease and a sixfold increase in the risk of developing diabetes (5). Thus, the metabolic syndrome is increasingly recognized as a diagnostic entity that requires medical intervention.

The definition of metabolic syndrome does not, however, include cardiovascular risk factors such as smoking. Furthermore, other indicators of aggregate risk factor burden, such as the Framingham score (see "Taking the Long View"), may be better predictors of cardiovascular disease than a diagnosis of the metabolic syndrome (3). This means that the metabolic syndrome might be considered as a diagnosis that complements, but does not replace, traditional methods of cardiovascular risk assessment.

Although the metabolic syndrome is associated with other factors that increase the risk of cardiovascular disease, such as increased inflammation and thrombogenicity (2), these factors are not part of the existing definitions of the syndrome. Increased inflammation can increase insulin resistance, thereby worsening components of the syndrome. Thus, inflammatory markers such as high-sensitivity C-reactive protein may add predictive value to metabolic syndrome (6).

Defining the Metabolic Syndrome

Over the years, several groups have developed criteria to define the metabolic syndrome. They include the World Health Organization (WHO), the European Group for the Study of Insulin Resistance (EGIR), the National Cholesterol Education Program (NCEP), the Adult Treatment Panel III (ATPIII), the International Diabetes Federation, and the American Association of Clinical Endocrinologists (AACE). The proposed criteria are similar but have some important differences. Those developed by WHO and EGIR include measures of insulin resistance, whereas the others do not. In addition, criteria by EGIR and AACE exclude diabetes because the metabolic syndrome is thought to be a precursor to diabetes; the criteria developed by other groups include it in their definitions. The AACE criteria use body mass index (BMI) as a measure of adiposity, whereas the other criteria emphasize waist circumference because of the importance of abdominal obesity as a cardiovascular risk factor. In general, the criteria differ on the specific cutpoints used for waist circumference and blood pressure and concentrations of triglycerides, HDL, and glucose.

The American Heart Association (AHA) and the National Heart, Blood, and Lung Institute (NHLBI) at the National Institutes of Health recently published a statement to harmonize existing criteria for the metabolic syndrome and formulated new ones (3) According to their definition, which reflects minor modifications from that of the ATPIII, the metabolic syndrome has to meet three of the following five criteria: (i) elevated waist circumference, defined as ≥102 cm for men and ≥88 cm for women; (ii) triglyceride concentrations ≥150 mg/dl, or drug treatment for elevated triglycerides; (iii) HDL concentrations >40 mg/dl for men and >50 mg/dl for women, or drug treatment for low HDL; (iv) systolic blood pressure ≥130 mmHg and diastolic blood pressure ≥85 mmHg, or drug treatment for hypertension; (v) fasting glucose concentrations ≥100 mg/dl, or drug treatment for elevated glucose.

The definition has some limitations. It does not take into account racial and ethnic differences in susceptibility to increased adiposity. For example, Asians require smaller increases in abdominal fat and waist circumference to develop insulin resistance, as compared with Europeans (1). Furthermore, it does not include a direct measure of insulin resistance but instead assumes that the measurement of waist circumference and of fasting glucose concentrations will capture this parameter. Direct measures of insulin resistance, such as fasting insulin concentrations, may be all the information that is needed to predict risk of diabetes and cardiovascular disease (7). In addition, the risk factors that comprise the metabolic syndrome may have a linear association with atherosclerotic cardiovascular disease: that is, the higher the degree of risk factors (such as blood pressure, lipids, glucose, and waist circumference), the higher the risk of disease. Thus, the use of cutoffs probably leads to misclassification of individuals as having or not having a criterion. Lastly, most of the evidence for the existing definitions of the metabolic syndrome comes from middle-aged populations, and work is needed to determine its clinical significance in other age groups, particularly the elderly.

Relevance of the Metabolic Syndrome to Cognition

Diabetes (8), hyperinsulinemia (9), and obesity (10) are increasingly recognized as risk factors for dementia and cognitive impairment. Thus, one would expect that the metabolic syndrome is also relevant to these conditions. One study found that the metabolic syndrome was associated with a higher risk of cognitive impairment, but only among elderly persons with a high degree of inflammation (11) (see "Pay by the Pound"). This observation underlines the potential importance of the metabolic syndrome beyond cardiovascular outcomes and the additional predictive value of measures of inflammation.

Treatment Options

Once a diagnosis of metabolic syndrome is made, treatment is primarily directed at the main, traditional vascular risk factors: hypertension (12), high serum concentrations of low-density lipoprotein (LDL) (13), and diabetes. However, by targeting the underlying causes, most often obesity, and insulin resistance (14), it might be possible to reverse the syndrome. In this respect, the first strategy should be to lose weight through caloric restriction and exercise. Pharmacological intervention should be a second option, with the caveat that there are no sufficiently proven modalities.

The Diabetes Prevention Program (DPP), a clinical trial of more than 3000 participants with glucose intolerance at increased risk of diabetes and cardiovascular disease, examined the effects of intensive lifestyle intervention (through diet and exercise), the drug metformin (which reduces insulin resistance), or placebo. Lifestyle intervention was the most effective treatment for weight loss and for preventing diabetes, followed by metformin (15). The prevalence of the metabolic syndrome in DPP participants at baseline was 51%; lifestyle intervention reduced it by 41% and metformin by 17%. Both interventions have been shown to decrease inflammation and thrombogenicity (16), important factors associated with the metabolic syndrome and with increased cardiovascular risk.

Lifestyle Changes

The results of the DPP underline the power of lifestyle interventions in decreasing the prevalence of the metabolic syndrome and associated conditions that increase cardiovascular disease. In clinical trials, lifestyle interventions are highly structured and thus more likely to succeed than in real life, in which rigorous lifestyle interventions may be more difficult to achieve. This difficulty seems particularly relevant to elderly populations, in which individuals may have comorbidities that preclude effective lifestyle changes. In addition, patients have a tendency to regain some, though not all, of the weight lost after these interventions. An increasingly important and interesting challenge for physicians and researchers is to design and implement lifestyle and pharmacological interventions that can result in long-term maintenance of a healthy weight, insulin levels, and cardiovascular risk profile.

Metformin is approved by the Food and Drug Administration for the treatment of diabetes, whereas other uses are off-label. The primary action of metformin is to reduce liver neoglucogenesis (17), but its mechanisms are not fully understood. It is a safe drug, the most usual side effect being gastrointestinal intolerance. Thus, it may be reasonable to use metformin as an adjuvant to lifestyle interventions in persons with the metabolic syndrome and documented glucose intolerance.

Further details on the targets, goals, and therapeutic strategies for the management of components of the metabolic syndrome are beyond the scope of this Perspective. These are, however, summarized in the recent AHA/NHLBI statement (3). The Joint National Committee on the Prevention, Detection, and Treatment of Hypertension (12), NCEP (13), and the American Diabetes Association (18) provide specific guidelines for treating hypertension and diabetes and maintaining healthy lipid concentrations.

Conclusion

The metabolic syndrome defines the clustering of several risk factors for atherosclerosis and diabetes. Its most likely cause is insulin resistance and high adiposity, but its origin may be heterogeneous and, in some cases, its presence may simply reflect the coexistence of common disorders. Although current definitions of the metabolic syndrome use fixed cutoff points for a number of parameters, these may be misleading when making a diagnosis. Many parameters, such as glucose concentrations and abdominal adiposity, vary among different individuals and particularly among ethnic groups. Treatment of the underlying causes of the metabolic syndrome may prevent diabetes and atherosclerotic heart disease. Such treatment should not replace existing strategies to treat traditional atherosclerosis risk factors, such as diabetes, hypertension, dyslipidemia, and smoking, but instead should complement such treatments.

The first strategy in the treatment of the metabolic syndrome should be lifestyle interventions. There are no accepted pharmacologic modalities to treat the metabolic syndrome, although the drug metformin may be a good candidate. The metabolic syndrome as a diagnostic entity is a work in progress, and its definition and treatment will likely change in the near future.


June 28, 2006
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Citation: J. A. Luchsinger, A Work in Progress: The Metabolic Syndrome. Sci. Aging Knowl. Environ. 2006 (10), pe19 (2006).








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