Pro: Yes, It Is Clinically Useful to Identify Metabolic Syndrome as a Real Syndrome

As a construct that denotes risk factor clustering, metabolic syndrome has been a useful paradigm; it draws attention to the fact that some cardiovascular disease (CVD) risk factors tend to cluster in predisposed patients. It is clinically important to identify metabolic syndrome as a true syndrome, as identification of one of the risk variables in a patient should prompt a search for others. Metabolic syndrome is a collection of metabolic abnormalities that result in a predisposition to developing diabetes mellitus and CVD. To be diagnosed with metabolic syndrome, a patient must meet at least three out of five criteria: central obesity (waist circumference, body mass index [BMI], visceral adiposity), low high-density lipoprotein (HDL), elevated triglycerides, fasting glucose ≥100 mg/dL or on hypoglycemic medication, and moderately elevated blood pressure or hypertension. Metabolic syndrome is a true multifaceted syndrome because there is a common underlying pathology that links all of the symptoms and risk factors together, with ultimate disease manifestation as CVD or diabetes mellitus.

A current theory focuses on insulin resistance as the unifying component that ties all these metabolic abnormalities together. With increased adipose tissue due to obesity, an excess of circulating free fatty acids stimulate the liver to produce more triglycerides and LDL while decreasing HDL production, resulting in hyperlipidemia. The free fatty acids cause insulin resistance by inhibiting insulin-mediated glucose uptake in the skeletal and cardiac muscle, resulting in hyperglycemia. The pancreas compensates for the high glucose serum levels by producing more insulin, which results in a hypertensive response by the kidney. This disease process becomes a vicious cycle as insulin resistance results in increased lipolysis and fatty acid production. This further exacerbates the hyperlipidemia, hyperglycemia, and hypertension associated with pathologic metabolic syndrome.

Both exogenous and endogenous factors predispose an individual to developing metabolic syndrome, making it clinically relevant to identify this as a complete disease process. Environmental components that increase the risk of obesity (i.e., sedentary lifestyle and diet) can be considered the exogenous factors that relate to the development of metabolic syndrome. Endogenous factors include endocrine disorders and susceptibility to developing insulin resistance. Family history of obesity, diabetes, and CVD increases an individual's risk for developing metabolic syndrome.

It is clinically beneficial to classify metabolic syndrome as a true syndrome (some have used the ICD code of 277.7) so patients can be officially diagnosed in a universal manner that can motivate patients and physicians alike to manage accompanying risk factors. Currently, risk stratification for metabolic syndrome can be accomplished by looking at family history and personal health status. Future research can work towards developing a genetic screen for metabolic syndrome. However, this step in research depends on the acceptance of metabolic syndrome as a real syndrome to generate true patient cohort. With the development of genetic screening for metabolic syndrome, we can identify patients with a predisposition for the disease earlier and prevent adverse health outcomes from cardiovascular disease and diabetes mellitus.

By identifying those at risk of metabolic syndrome and these adverse outcomes, we can develop prevention and intervention strategies to improve patient health. The Diabetes Prevention Program in 2002 demonstrated that through lifestyle modifications in at-risk patients, such as exercise and a diet low in fat and calories, can reduce the risk of developing diabetes by 58%. Since diabetes mellitus is a component of metabolic syndrome (although some prefer to separate out those with frank diabetes, which has specific treatment guidelines separate from those with metabolic syndrome who do not have diabetes), this study serves as an application for treatment of patients who are susceptible to metabolic syndrome.

In June 2013, the American Medical Association labeled obesity as a "multi-metabolic and hormonal disease state." If this is considered a disease state, then metabolic syndrome should be considered a true syndrome of correlated metabolic abnormalities. The negative health outcomes of metabolic syndrome are significant. Patients with metabolic syndrome have been reported to have a two-fold increase in risk for heart attack and stroke as well as a five-fold increase for developing diabetes mellitus compared to patients without metabolic syndrome. This dramatically increased risk emphasizes the clinical importance of identifying metabolic syndrome as a true syndrome, as well as diagnosing patients with it earlier on to minimize the risks and begin preventive treatment.

Con: No, It Is Not Clinically Useful to Identify Metabolic Syndrome as a Real Syndrome.

The definition of syndrome is an "aggregate of symptoms and signs associated with any morbid process, and constituting together the picture of the disease." The specific symptoms and signs should be caused by an underlying pathology, and their combination should confer a risk that is different from the sum of the parts. For this reason, metabolic syndrome requires much more study before being designated a syndrome and before its clinical utility is established.

The definition is loosely defined. Just how clear is the existing definition of metabolic syndrome for diagnostic purposes? Different definitions have been developed by a number of medical organizations like the World Health Organization (WHO), National Cholesterol Education Program's Adult Treatment Panel III (ATP III), and the International Diabetes Federation (IDF). There are 16 different ways according to the ATP III definition and 11 different ways according the IDF definition to diagnose the metabolic syndrome (differing in their ranking of the order of importance), and each combination defines a different risk. Furthermore, in comparison between the ATP III and WHO definitions, there are metabolic criteria that are ambiguous or incomplete. First, it is not specified how blood pressure should be measured, e.g., supine, sitting, or the mean of two measurements. Also, there is no widespread agreement on the method for measuring waist circumference and whether it should be measured routinely. All in all, such ambiguities affect the sensitivity and specificity of the diagnosis and have led physicians to diagnose metabolic syndrome in patients who may have had a different diagnosis under another provider.

Underlying pathophysiology is unclear. Insulin resistance is considered to be a key pathogenic factor in the development of certain features of metabolic syndrome, such as high sugar levels, abnormal cholesterol levels, and, to an extent, increased blood pressure. However, insulin resistance may simply be one of many abnormalities linked to a more unifying pathophysiology. Other factors which should be considered due to their contribution to diabetes mellitus and CVD include the involvement of cytokines (e.g., C-reactive protein), adipose tissue abnormalities (adiponectin), genetic factors, disordered hypothalamic-pituitary-adrenal axis, altered glucocorticoid action, physical activity, and stress. In addition, obesity is often linked to insulin resistance; however, not all insulin resistant individuals are overweight. Therefore, patients could have this set of signs and symptoms due to different diseases because of overlapping risk factors, not a connecting pathophysiologic mechanism.

Treatment is focused on singling out each risk factor rather than a whole. Until randomized controlled trials have been completed, there is no appropriate pharmacological treatment for the metabolic syndrome, nor should it be assumed that pharmacological therapy to reduce insulin resistance will be beneficial to patients with the metabolic syndrome.

Value of making the diagnosis is uncertain. One study related metabolic syndrome and its five individual components to the risk of events of incident CVD and type 2 diabetes in 4,812 non-diabetic individuals aged 70-82 years from the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) trial. This data was corroborated in a second prospective study (the British Regional Heart Study [BRHS]) of 2,737 non-diabetic men aged 60-79 years.

In PROSPER, metabolic syndrome was not found to be associated with an increased risk of CVD in those with and without existing CVD, but was associated with an increased risk of diabetes as was each of its components, particularly fasting glucose. Similarly, in BRHS, metabolic syndrome was modestly associated with incident CVD (relative risk 1.27 [1.04-1.56]) despite strong association with diabetes. In both studies, BMI or waist circumference, triglyceride, and glucose cutoff points were not associated with risk of CVD, but all five components were associated with risk of new-onset diabetes.

This study showed that metabolic syndrome and its components are associated with type 2 diabetes but have weak or no association with vascular risk in elderly populations, suggesting that attempts to define criteria that simultaneously predict risk for both CVD and diabetes are unhelpful. Furthermore, a 2010 study published in The Journal of the American College of Cardiology by Mottillo et al. showed that patients with metabolic syndrome, but without diabetes, maintained a high cardiovascular risk, indicating the current insulin resistance theory as a unifying component tying all these metabolic abnormalities is not necessarily true. A simple fasting plasma glucose measurement is a much better predictor of future diabetes than the expense and inconvenience necessary to diagnose the syndrome.

In summary, providers should avoid labeling patients with the term "metabolic syndrome," as this might create the impression that the metabolic syndrome denotes a greater risk than its components, or that it is more serious than other CVD risk factors, or that the underlying pathophysiology is clear. Without high-quality evidence, it is premature to introduce metabolic syndrome as a distinct entity in clinical medicine or incorporate it into public health policy. It is important to treat the individual risk factors and diseases and encourage lifestyle modifications such as proper diet and exercise.

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References

1. Eckel R. Chapter 242: The Metabolic Syndrome. In: Longo DL, Fauci AS, Kasper DL, et al. eds. Harrison's Principles of Internal Medicine, 18e. New York, NY: McGraw-Hill; 2012.
2. Grundy S, Smith S. Chapter 92: Metabolic Syndrome, Obesity, and Diet. In: Fuster V, Walsh RA, Harrington RA. eds. Hurst's The Heart, 13e. New York, NY: McGraw-Hill; 2011.
3. Kahn R, Buse J, Ferrannini E, Stern M. The metabolic syndrome: time for a critical appraisal: joint statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2005; 28:2289-304.
4. Knowler W, Barrett-Connor E, Fowler S, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002; 346: 393-403. Mottillo S, Filion K, Genest J, et al. The metabolic syndrome and cardiovascular risk. J Am Coll of Cardiol 2010;56:1113-32.
5. NIH Staff. Metabolic Syndrome. National Heart, Lung, and Blood Institute. http://www.nhlbi.nih.gov/health/health-topics/topics/ms/causes.html. Published November 3, 2011. Accessed March 31, 2014.
6. Sattar N, McConnachie A, Shaper A, et al. Can metabolic syndrome usefully predict cardiovascular disease and diabetes? Outcome data from two prospective studies. Lancet 2008 Jun 7;371:1927-35.

Keywords: Metabolic Syndrome, Cardiovascular Diseases

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