What’s in a name?

Reflections on the (suddenly) controversial ‘metabolic syndrome.’

Issue: January 2006

ByStephen Brieztke, MD

Stephen A. Brietzke, MD
Stephen A. Brietzke

In his 1988 Banting Lecture, Reaven introduced version 1.0 of what most of us now call the metabolic syndrome as “Syndrome X” — at once a mysterious, sinister, and ominous-sounding (almost sci-fi) name for a constellation of cardiovascular risk factors that include type 2 diabetes mellitus, hypertension and dyslipidemia (low HDL cholesterol accompanied by hypertriglyceridemia and atherogenic small dense LDL particles).

He postulated that these findings, which group more commonly than one would expect by chance alone, were etiologically linked by underlying insulin resistance. “Syndrome X,” as a name, suffered from a competing “syndrome X” used by cardiologists to describe patients with classic angina pectoris with angiographically-normal epicardial coronary arteries; versions 2.0 and higher have given us the alternative names of “metabolic syndrome” and, most recently, “cardiometabolic syndrome.”

Diagnostic criteria

Legitimacy for the concept of metabolic syndrome has been afforded by the Adult Treatment Panel (ATP-III) of the National Cholesterol Education Program, which offers diagnostic criteria for metabolic syndrome as at least three of the following diagnostic criteria:

waist circumference >102 cm in men, or >88 cm in women (surrogate for “central adiposity”);
serum triglycerides >1.7 mmol/L;
serum HDL cholesterol <1.0 mmol/L in men, or <1.3 mmol/L in women;
blood pressure >130/85 mmHg; and
serum glucose >6.1 mmol/L (or maybe >5.6 mmol/L).

The World Health Organization offers similar but slightly different criteria to include the presence of dysglycemia (DM, impaired fasting glucose, impaired glucose tolerance, or insulin resistance [as ascertained by clamp studies]) and at least two additional criteria of:

waist-to-hip ratio >0.9 in men or >0.85 in women;
serum triglycerides >1.7 mmol/L or HDL-c <0.9 mmol/L in men and <1.0 mmol/L in women;
blood pressure >140/90 mmHg; and
urinary albumin excretion >20 mcg/min or albumin-to-creatinine ratio >30 mg/gm.

For practicing clinicians, an even more important contributor to the legitimacy of metabolic syndrome as an entity was its recognition as a unique ICD-9 code 277.7; if one can bill for it, surely it must exist!?

But, not so fast! Consider the definition of “syndrome” offered by the Merriam-Webster dictionary: 1) a group of signs and symptoms that occur together and characterize a particular abnormality; or 2) a set of concurrent things that usually form an identifiable pattern. For the former, endocrinologists readily identify a symptom constellation of proximal muscle weakness, anxiety or depression, moon facies, dorsal cervical and supraclavicular fat pads, and deep violaceous cutaneous striae as Cushing syndrome — which in turn may be due to a number of specific causes of hypercortisolism.

Nephrologists recognize the nephrotic syndrome as heavy proteinuria, edema and hyperlipidemia, and are aware that a number of different glomerular diseases can produce this easily-recognizable constellation of symptoms and signs.

In either of these familiar examples, the ideal treatment targets the root cause; however, pragmatic management often addresses individual components of the syndromes (eg, statin drugs for nephrotic hyperlipidemia; diuretics for edema; antidepressants for Cushing-related dysphoria). That individual components of the syndromes can be treated without addressing the syndrome at its root cause has not led to any widespread move to disavow recognition of either Cushing or nephrotic syndrome, as syndromes.

Term questioned

In contrast, in September 2005 the American Diabetes Association and the European Association for the Study of Diabetes issued a joint statement distancing their organizations from the concept of metabolic syndrome. The statement cautions that there is as yet no strong evidence that treatments targeting the putative root cause of metabolic syndrome — insulin resistance — produce any outcomes benefit superior to treatments targeting the individual component disorders of diabetes, hypertension, dyslipidemia and obesity. The thoughtfully worded review questions even whether or not the pathophysiology of the metabolic syndrome has been sufficiently unraveled, citing tangible concerns as to the role of inflammation (markers include highly-sensitive C-reactive protein) and adipokines (notably, adiponectin).

The review further argues that the presence of metabolic syndrome, in the absence of diabetes mellitus, performs no better in the 10-year risk prediction of cardiovascular disease than does each of the component diseases (hypertension and dyslipidemia) and traditional risk factors such as smoking and family history of heart disease.

Further, the review fairly critiques the lack of consistent cut-off points between normal and abnormal insulin sensitivity and the crude clinical tools readily available to clinicians to ascertain the degree of insulin resistance in an individual patients.

Seems to be a syndrome

The points made in the joint ADA/EASD statement are well-taken and well-made. Yet for the clinician at Ground Zero in the daily counseling and risk assessment of patients, the concept of the metabolic syndrome seems an apt paradigm, reminding us that the patients at highest risk for cardiovascular disease have not just one or two, but multiple risk factors.

It is premature to advocate use of insulin-sensitizing agents as targeted root cause prevention (indeed, the PROactive trial of pioglitazone in secondary prevention of cardiovascular disease is largely negative in this regard) — but in the daily battle it is not premature to advocate more aggressive statin and antihypertensive therapy in these patients with multiple components of metabolic syndrome. It is perhaps not premature to employ HbA1c in comprehensive risk assessment, since there is a clear increase in CHD risk of approximately 20% as HbA1c rises from 5% to 6% in nondiabetic individuals.

That there is much yet to unravel in the pathophysiology of metabolic syndrome should not discourage the concept that there are unifying risk factors for the component diseases. Indeed, investigation into the roles of vascular inflammation, atherogenesis, and adipokine signaling in metabolic syndrome-associated cardiovascular disease should continue full-tilt in both the basic and translational sciences.

Thinking physicians who repeatedly see the same disorders in the same patients logically ask the question, “Are all these things coincidence or part of one larger disease?”

For many of us, it’s easier to think about multiple problems as having one root cause, or at least a common underlying complex pathophysiology. Hypertension, dysglycemia, dyslipidemia, and central obesity occur in the same patients more often than by chance alone.

Sounds a lot like a syndrome, doesn’t it? I for one am going to continue thinking about these problems that way.

For more information:

Stephen A. Brietzke, MD, is Associate Professor of Clinical Medicine in the Division of Endocrinology, Diabetes and Metabolism, University of Missouri Columbia School of Medicine and a member of Endocrine Today’s Editorial Board.

Reaven GM. Role of insulin resistance in human disease. Diabetes. 1988;37:1595-1607.

Grundy SM, Brewer HB Jr, Cleeman JI, Smith SC Jr, Lenfant C, National Heart, Lung, and Blood Institute, American Heart Association. Definition of metabolic syndrome: report of the National Heart, Lung, and Blood Institue/American Heart Association conference on scientific issues related to definition. Circulation. 2004;109:433-438.

World Health Organization. Definition, diagnosis, and classification of diabetes mellitus and its complications: report of a WHO consultation. Geneva, World Health Organization, 1999.

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.

Dormandy JA, Charbonnel B, Eckland DJ, Erdmann E. et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial in macroVascular Events): a randomized controlled trial. Lancet. 2005;366(9493): 1279-1289.

Khaw KT, Wareham N, Bingham S, Luben R, Welch A, Day N. Association of hemoglobin A1c with cardiovascular disease and mortality in adults: the European Prospective Investigation into Cancer in Norfolk. Ann Intern Med. 2004;141: 413-420.