Kahn R.

Metabolic syndrome- what is the clinical usefulness?

In today's Lancet, Naveed Sattar and co-workers put yet another nail in the coffin of the metabolic syndrome.1 Their analysis of longitudinal data from two independent population-based cohorts, which document the incidence of cardiovascular events or diabetes in elderly patients, shows that a fasting plasma glucose test is as good as or potentially better than a diagnosis of the metabolic syndrome for predicting diabetes. They also show that a diagnosis of the metabolic syndrome has negligible association with risk of cardiovascular disease; and that the whole is not greater than the sum of the parts. Thus diagnosis of the metabolic syndrome has no apparent clinical value.

In the joint statement from the American Diabetes Association and the European Association for the Study of Diabetes on the metabolic syndrome, eight major concerns were identified (panel).2 Since then, other commentaries support the concept of the metabolic syndrome3–5 or, conversely, provide additional perspectives that concerns raised in the statement were justified.5,6 Many other studies also affirm the difficulties outlined.7–10

Importantly, critics of the metabolic syndrome do not question or doubt the evidence that many risk factors of cardiovascular disease are found more often in combination than chance would dictate. Thus identification of one risk factor for cardiovascular disease in a patient should prompt the search for others—even those not in the syndrome's construct. Moreover, there is no argument that results from many studies show that metabolic syndrome factors by themselves, or in any combination, portend cardiovascular disease and many other adverse outcomes. It is well known that elevated blood glucose, obesity, increased blood pressure, or dyslipidaemia are serious.

Substantial evidence also shows that insulin resistance plays an important part in risk-factor clustering, and probably contributes in some way to many of the untoward outcomes attributed to the metabolic syndrome. Indeed, nearly everyone agrees that lifestyle modification is a helpful intervention for those who have one or any combination of the syndrome's components and other risk factors for cardiovascular disease or diabetes (eg, raised LDL cholesterol, smoking).

On the other hand, sceptics of the usefulness of the metabolic syndrome's construct would like evidence that diagnosis of an individual with the syndrome somehow focuses attention on the need for lifestyle therapy that would otherwise be ignored or missed. They would also like evidence that such a diagnosis informs clinicians that cardiovascular disease is a multiple risk-factor model of a form they would otherwise not know, or that the diagnosis conveys the seriousness of obesity in a way not currently appreciated. They would also like evidence that the diagnosis inspires patients to take action and be more adherent to therapy than if they were diagnosed with one or more risk factors, but not the metabolic syndrome. And that the diagnosis results in a treatment that would otherwise not be recommended for modifiable risk factors, and that the construct is a valuable risk-assessment method to identify patients at increased risk of cardiovascular disease or diabetes.

More than a decade since its formal introduction and thousands of papers later, these six propositions—promulgated by the proponents of the syndrome—remain no more than intriguing thoughts. However, the last argument—ie, metabolic syndrome is valuable for risk assessment and therefore its identification will improve patients' outcomes—is often considered as the syndrome's greatest strength.

That people with metabolic syndrome are at increased risk of cardiovascular disease events or diabetes does not mean that the construct is useful for risk prediction in itself or compared with other approaches. First, as reviewed by Pepe and colleagues,11 odds ratios or relative risks regarded as giving strong associations in observational studies (eg, odds ratios of 1·2–2·5) are inadequate to distinguish between people who do (will) or do not (will not) have the outcome of interest. Much stronger associations are needed (eg, =4·0). Second, many reports compare metabolic syndrome with much simpler risk-assessment tests for cardiovascular disease, and those risk-assessment tests are significantly better.2,6,7 Additionally, a simple fasting plasma glucose measurement is a much better predictor of future diabetes than the expense and inconvenience necessary to diagnose the syndrome.2,10

What seems to make most sense is for clinicians to focus on global risk assessment that takes into account all the well-established cardiometabolic risk factors (figure),13 and then to treat each abnormality appropriately. Also, more research is needed to understand the cause of risk-factor clustering and the pathogenesis of insulin resistance. Both actions would better serve the health of those at risk of diabetes and cardiovascular disease than seeking a diagnosis of the metabolic syndrome.

References

1. Sattar N, McConnachie A, Shaper G, et al. Can metabolic syndromes usefully predict cardiovascular disease and diabetes? Outcome data from two prospective studies. Lancet 2008;
2. 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: 2289-2304.
3. Grundy SM. Does a diagnosis of the metabolic syndrome have value in clinical medicine?. Am J Clin Nutr 2006; 83: 1248-1251.
4. Grundy SM. Metabolic syndrome: a multiplex cardiovascular risk factor. J Clin Endocrinol Metab 2007; 92: 399-404.
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6. Reaven GM. The metabolic syndrome: is this diagnosis necessary?. Am J Clin Nutr 2006; 83: 1237-1247.
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8. Iribarren C, Go AS, Husson G, et al. Metabolic syndrome and early-onset coronary disease: is the whole greater than the sum of its parts?. Am Coll Cardiol 2006; 48: 1800-1807.
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10. Cull CA, Jensen CC, Retnakaran R, Holman RR. Impact of the metabolic syndrome on macrovascular and microvascular outcomes in type 2 diabetes mellitus: United Kingdom Prospective Study 78. Circulation 2007; 116: 2119-2126.
11. Pepe MS, Janes H, Longton G, Leisenring W, Newcomb P. Limitations of the odds ratio in gauging the performance of a diagnostic, prognostic, or screening marker. Am J Epidemiol 2004; 159: 882-890.
12. Brunzell JD, Davidson M, Furberg CD, et al. Lipoprotein management in patients with cardiometabolic risk: consensus statement from the American Diabetes Association and the American College of Cardiology. Diabetes Care 2008; 31: 811-822.
13. Eckel RH, Kahn R, Robertson RM, Rizza RA. Preventing cardiovascular disease and diabetes: a call to action from the American Diabetes Association and the American Heart Association. Diabetes Care 2006; 29: 1697-1699.