Med Clin N Am 88 (2004) 837846

The metabolic syndrome

Alan J. Garber, MD, PhDa,b,*
a

Departments of Medicine, Biochemistry and Molecular Biology, and Molecular and Cellular Biology, Baylor College of Medicine, 6550 Fannin Street, Suite 1045, Houston, TX 77030, USA b Department of Endocrinology, Diabetes, and Metabolism, The Methodist Hospital Houston, TX, USA

The metabolic syndrome is a collection of frequently associated cardiovascular risk factors that tend to aggregate in selected patient populations and that, together, increase coronary and cardiovascular mortality, and total mortality. The term metabolic syndrome has been used variously by disparate organizations to connote dierent entities. Some, such as the World Health Organization, have used this term to indicate a state of insulin resistance with pervasive dysmetabolism secondary to the state of insulin resistance. Conceptualization of the metabolic syndrome as a unique, highrisk cardiovascular state, as dened by the National Cholesterol Education Program (NCEP), is gaining acceptance as the basis for diagnosing the metabolic syndrome [1]. The NCEP denition is based on clustering multiple metabolic abnormalities associated with insulin resistance but does not require a measure of insulin sensitivity. Table 1 cites the current criteria for the diagnosis of the metabolic syndrome, according to NCEP guidelines. A diagnosis is made by the presence of three or more abnormalities. Although each abnormality may be associated with underlying insulin resistance, no requirement exists for an experimental demonstration of insulin resistance or a measurement of impaired insulin-mediated glucose disposal. Several of these clinical features, such as low high-density lipoprotein (HDL) cholesterol levels and elevations of triglyceride-rich lipoproteins in fasting serum specimens, are well known to be interrelated. Furthermore, these conditions also tend to be more prevalent in obese individuals as well as in those with essential hypertension, making this syndrome increasingly prevalent in patients with one or more traditional risk factors for cardiovascular disease.

* Baylor College of Medicine, 6550 Fannin Street, Suite 1045, Houston, TX 77030. E-mail address: agarber@bcm.tmc.edu 0025-7125/04/$ - see front matter 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.mcna.2004.04.001

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Table 1 Denition of metabolic syndrome Risk factor Abdominal obesity Men Women Triglycerides HDL cholesterol Men Women Blood pressure Fasting glucose NCEP criteria (any 35 symptoms). Dening level Waist >40 inches Waist >35 inches 150 mg/dL \40 mg/dL \50 mg/dL 130/85 mm Hg 110 mg/dL

The metabolic syndrome, as dened by the NCEP, is not to be confused with the insulin resistance syndrome or the presence of underlying insulin resistance, although such resistance is likely in patients with the metabolic syndrome. Insulin resistance is an evolving entity, which may or may not be associated with aspects of dysmetabolism secondary to prolonged insulin resistance that appear later. A useful example of this evolution is the slow, progressive decline of pancreatic b-cell function under conditions of ongoing or worsening insulin resistance. This decline leads ultimately to hyperglycemia and a clinical diagnosis of type 2 diabetes. Many years are required for the evolution of this process before diabetes can be diagnosed [2]. There is, therefore, an antecedent period of compensated hyperinsulinemic euglycemia in which patients clearly are insulin resistant but in whom dysmetabolism of carbohydrates may be dicult to detect. A similar latency may also exist with respect to the evolution of dyslipidemia secondary to impaired clearance of triglyceride-rich lipoproteins or accelerated removal or delayed synthesis of HDL cholesterol. For example, teenaged women with polycystic ovary syndrome clearly have, as part of the underlying pathogenesis of this disorder, an important element of insulin resistance. However, at the time of diagnosis, these young women rarely have obvious hypertriglyceridemia, low HDL cholesterol, or overtly abnormal carbohydrate metabolism. With prolonged persistence of unrelieved insulin resistance, however, they do have a much higher likelihood of developing the stigmata of the metabolic syndrome. Thus, it may therefore be possible that the metabolic consequence of early b-cell failure in the presence of prolonged insulin resistance leads to the abnormal metabolism required to diagnose the metabolic syndrome. A weaker association exists between insulin resistance and essential hypertension. Various authors have concluded that approximately 50% to 75% of patients with essential hypertension have underlying insulin resistance. Whether such resistance begins before the onset of hypertension is somewhat unclear, although obesity is a clear risk factor for the

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development of hypertension, and obesity is also a risk factor for the development of insulin resistance. It is likely that the insulin resistance precedes the hypertension in such cases, although not in all cases of essential hypertension, even when hypertension is fully developed. Although it is currently under reexamination, impaired fasting glucose (a fasting glucose 110 mg/dL) is one of the ve diagnostic criteria used for determining the presence of the metabolic syndrome. In contrast, some authors have suggested that patients with otherwise normal fasting glucose levels may demonstrate impaired glucose tolerance at the point of a 2-hour postglucose challenge, during an oral glucose tolerance test. Although a recent consensus development conference of the American College of Endocrinology recommended the inclusion of a 2-hour postglucose value of greater than 140 mg/dL as a potential alternative to the 110-mg/dL fasting glucose level, this addition has not been included in current denitions of the metabolic syndrome because glucose tolerance testing is believed to be too dicult for practitioners and potentially impractical in routine clinical settings. However, physicians may wish to oer such testing where possible to clarify patient status with the metabolic syndrome and to ascertain potential impairments of carbohydrate metabolism or even overt diabetes. Suggestions have been made to modify diagnostic criteria for the metabolic syndrome by including elevated levels of highly sensitive Creactive protein as a potential criterion for the diagnosis of the metabolic syndrome [3]. Although individuals with three or more criteria for metabolic syndrome were clearly shown to have increased levels of C-reactive protein, such elevations of C-reactive protein may not be independent of the underlying insulin resistance, which is surely present in patients having three or more diagnostic features of the metabolic syndrome. Thus, the use of elevated C-reactive protein may overlap existing diagnostic components and, therefore, may not add additional insight about the nature of any underlying dysmetabolism. Instead, the use of highly sensitive C-reactive proteins as an additional estimate of cardiovascular risk, independent of the underlying diagnosis of the metabolic syndrome, should be retained as potentially more useful than by its inclusion within the metabolic syndrome. A diagnosis of the metabolic syndrome is, however, tantamount to a diagnosis of excess cardiovascular risk, whether or not C-reactive proteins are elevated. In the Nurses Health Survey, event-free survival in individuals with the metabolic syndrome was clearly lower than in individuals without the metabolic syndrome [2]; however, it should also be noted that individuals with elevated C-reactive protein and a diagnosis of metabolic syndrome had even lower rates of event-free survival than did individuals with the metabolic syndrome but with low levels of C-reactive protein. Thus, a diagnosis of the metabolic syndrome based on the criteria of the NCEP is highly eective in predicting excess cardiovascular risk. For example, in an analysis of the Framingham Study ospring, diagnosis of the metabolic syndrome approximately doubled cardiovascular risk for males

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and tripled such risk for females with the metabolic syndrome compared with those without the metabolic syndrome. A greater adverse cardiovascular impact of the metabolic syndrome was seen by Lakka et al [4] in the Kuoppio Study (see [4]), in which a diagnosis of the metabolic syndrome increased coronary artery mortality and cardiovascular mortality by threefold and doubled total mortality in this patient population. An even greater cardiovascular risk was noted in the Mexico City Study. The metabolic syndrome may also be an outstanding risk predictor of future diabetes. In the Framingham Ospring Study, a recent analysis suggested that a diagnosis of the metabolic syndrome predicted a vefold 8-year future risk of diabetes in males and a sixfold increase in the future risk of diabetes in females. Although the accuracy of the metabolic syndrome as a predictor of excess risk of cardiovascular disease is not surprising, its robust ability to predict an excess risk of future diabetes is, in fact, somewhat unexpected. This degree of accuracy may provide insight into the precise nature of the metabolic syndrome. Because it is likely that the metabolic syndrome describes at least one aspect of underlying insulin resistance (clearly the period in which multiple metabolic abnormalities have evolved, likely secondary to b-cell failure resulting from an underlying insulin resistance state), then the metabolic syndrome presents a slice in time in the evolution of the insulin resistant state into an area of gross pathology, such as type 2 diabetes or clinical atherosclerosis. Therefore, the metabolic syndrome likely characterizes a state in time of latent underlying disease evolution that may be viewed as preclinical diabetes or preclinical atherosclerosis. Based in large measure on epidemiologic analyses, such a diagnosis clearly represents a high probability transition state in the evolution from normality to gross pathology resulting from insulin resistance. It is important to recognize a transition state because transition states are generally more reversible than end-stage pathology. Alternatively, one may view the high predictability of the metabolic syndrome of future type 2 diabetes as the likelihood that the metabolic syndrome is already type 2 diabetes. This view derives from the observation that glucose is a continuous variable that proceeds from completely normal to completely abnormal, with the diagnosis of diabetes being a somewhat arbitrary event in the middle of this evolution. Prior expert committees have set arbitrary diagnostic criteria for type 2 diabetes at levels of 126 mg/dL, based in part on the recognized increase in the development of the typical or classic microvascular complications of diabetes, such as retinopathy. Nonetheless, although it is an expert opinion, the diagnosis point for diabetes remains arbitrary. This is not to say that diabetes may not occur at an earlier point or at lower glucose levels before the development of very substantial rates of hyperglycemia. As seen in the special analysis of the NHANES III database, there was a vefold increase in the incidence of retinopathy in the fasting glucose interval of 110 to 119 mg/dL compared with the interval of 100 to 109 mg/dL. It is therefore

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possible that much lower levels of fasting hyperglycemia may be associated with milder degrees of type 2 diabetes than the level currently used for the diagnosis of type 2 diabetes (126 mg/dL). Similarly, the United Kingdom Prospective Diabetes Study (UKPDS) used a fasting glucose level of 108 mg/dL to diagnose diabetes and encountered a 21% incidence of retinopathy in their newly diagnosed patients [5]. The metabolic syndrome may overlap, to a variably greater extent, the diagnosis of type 2 diabetes and may ultimately be replaced by a more aggressive diagnosis of this disorder. The prevalence of the metabolic syndrome is truly staggering. Although there may be an epidemic of type 2 diabetes in the United States, the proportion of Americans with the metabolic syndrome is far larger. Using the criteria of the NCEP and applied to the results of the NHANES III database updated to the 2000 census, Ford et al [6] estimated that approximately 47 million Americans met the current criteria of the metabolic syndrome. As high as 40% of the population 60 years and older have the metabolic syndrome. The syndrome is higher in minority patients compared with white patients. The number of Americans with the metabolic syndrome clearly exceeds the number of Americans with type 2 diabetes and those with impaired glucose tolerance. Thus, the number at risk for the future development of type 2 diabetes is much greater than previously suspected. Indeed, the striking prevalence of the metabolic syndrome in the US population, together with its extraordinary predictability of future diabetes, may be a useful rationale for aggressive interventions with regard to treatment of the metabolic syndrome, not only as a high-risk cardiovascular state, but also, as a serious premonitory state of type 2 diabetes. Either or both of these views clearly justies intervention, both with regard to hygienic measures, such as lifestyle modication including diet and exercise, together with the possibility of pharmacologic intervention to interdict the evolution to type 2 diabetes and to mitigate the excess risk of cardiovascular events.

Obesity The foundation of the metabolic syndrome is excess deposition of adipose tissue in visceral or abdominal compartments, which gives rise to an underlying insulin resistant state. Although the NCEP denition of the metabolic syndrome does not directly measure insulin sensitivity, much of the diagnostic criteria outlined previously are associated with the dysmetabolism of insulin resistance. Insulin resistance may be directly addressed by lifestyle modication. Such modications include regular, vigorous aerobic exercise as frequently as possible. The insulin sensitizing benets of exercise require, for example, ve or more sessions per week of approximately 3 to 5 miles per day, consisting of a brisk walking pace of 3 to 4 miles per hour. Light-weight training is also useful in supporting muscle bulk and assisting with weight reduction. Of course, before

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beginning regular daily exercise, patients with high risk of coronary disease should undergo exercise cardiac testing to exclude subclinical or atypical coronary ischemia. Exercise alone without aggressive calorie restriction is usually insucient to produce weight loss. Indeed, exercise may increase appetite, which may more than compensate for the increased caloric expenditure and oxygen consumption associated with the exercise. For that reason, aggressive dietary modication with limitation of concentrated sweets, saturated fats, and reduction of portion sizes seems essential if weight reduction is to be achieved. Weight reduction to achieve a body mass index (BMI) less than 30 is essential if the metabolic syndrome is to be modied. Nonobese but overweight individuals have a substantially reduced risk of the metabolic syndrome. Of course, reduction of overweight individuals to normal weight (27 BMI) would be ideal, but this level may be dicult to achieve in the markedly obese population in whom even small degrees of weight loss would be benecial for many of the parameters of the metabolic syndrome, especially the hypertriglyceridemia and hyperglycemia. Lifestyle modication with diet and exercise greatly magnies the eect of pharmacologic agents designed to intervene in dyslipidemia, hypertension, or abnormal carbohydrate tolerance. Because the metabolic syndrome is also a high-risk predictor of future diabetes, intervention to prevent the development of overt type 2 diabetes seems appropriate. The role of diet and exercise as part of a thorough lifestyle modication program is unsurpassed for prevention of type 2 diabetes in patients with impaired glucose tolerance. Although they are not strictly the same as the patient population with the metabolic syndrome, patients in the Diabetes Prevention Program (DPP) showed a 58% reduction in the risk of development of type 2 diabetes by a 7% loss of body weight and regular daily exercise. Pharmacologic therapies were also useful for the prevention of type 2 diabetes because these therapies may have reduced the underlying insulin resistance. These therapies, however, will be discussed later as part of future considerations in the management of the metabolic syndrome. Pharmacologically assisted weight loss may also be considered. Orlistat (Xenical) therapy reduces fat absorption, produces a 3% to 8% weight loss, and reduces the development of type 2 diabetes. It should be considered for those failing life style modications.

Treatment of dyslipidemia The metabolic syndrome does not necessarily include hypercholesterolemia, as characterized by a markedly increased mass of low-density lipoprotein (LDL) cholesterol. Instead, a shift in the size distribution of LDL particles toward a smaller, denser and inherently more atherogenic LDL particle, as the result of the underlying insulin resistance state, seems

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present in many of these patients. Diagnosis that focuses on hypertriglyceridemia and low HDL cholesterol levels aids in recognizing that these factors traditionally herald the presence of a severe, underlying redistribution of LDL particle size toward a smaller, more atherogenic particle size. Because patients with the metabolic syndrome represent a high-risk cardiovascular state, precise quantitation of this state by assessment of the 10-year cardiovascular risk using the Framingham risk engine (found on the NHLBI website) is most useful in determining appropriate action regarding reduction of LDL mass. Risks greater than 20% per 10 years equate to an extremely high risk state, equivalent to the risk of known coronary disease, and therefore merit reduction of LDL cholesterol below 100 mg/dL, using interventions with statins. Use of a statin should not be predicated on a titration of slight elevations to just below 100 mg/dL. Instead, if the decision is made to intervene with a b-hydroxy-b-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor, then a full dose, designed to produce a 30% to 40% reduction of LDL mass, such as 40 mg of pravastatin or simvastatin, should be used. This recommendation reects, in part, results from randomized controlled trials demonstrating that such doses customarily produce a signicant reduction in coronary events of approximately 30% or more and also the recognition that in high-risk patients with minimally elevated LDL levels there may likely be an altered particle distribution of LDL cholesterol, which may merit a somewhat more aggressive therapeutic intervention. For example, in the Heart Protection Study, patients with LDL cholesterol less than 100 mg/dL at the time of randomization beneted equally from 40 mg of simvastatin, with proportionate reductions in coronary event reduction, as did those patients with substantially higher levels of LDL cholesterol at the time of randomization to simvastatin. Once LDL goals have been attained, then residual elements of the dyslipidemia should be addressed. The second treatment goal for the management of dyslipidemia should be correction of low levels of HDL cholesterol. This goal may be attained by lowering triglycerides with a bric acid derivative if these triglycerides are substantially elevated (250 mg/dL). Previously, the use of gembrozil was encouraged, owing to the publication of two large-scale interventional trials demonstrating coronary event reduction with gembrozil. Recently, however, it has been recognized that gembrozil inhibits the glucuronidation of many statins thereby raising statin blood levels, resulting in elevated serum levels of such statins. This may considerably complicate safety considerations in the use of gembrozil in patients already treated with HMG-CoA reductase inhibitors. Thus, in such patients, fenobrate (Tricor) is preferred. The smallest possible dose that produces acceptable modication of triglyceride levels should be used. In those patients with low HDL cholesterol (40 mg/dL in males; 50 mg/dL in females) in whom triglycerides are not markedly elevated, direct intervention with nicotinic acid may be useful. Generally, for every 1 g of

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nicotinic acid administered, a 10% increase in HDL cholesterol can be expected. Nicotinic acid, used as part of a treatment program with statins, has produced remarkable event reductions in trials such as HATS. Presently, combination therapy tablets using lovastatin and slow-release nicotinic acid are available and prove eective for correcting dyslipidemia in patients with the metabolic syndrome. Treatment with nicotinic acid should be initiated and titrated slowly to avoid precipitating overt symptomatology secondary to the vasoreactive eects of nicotinic acid or to suddenly decompensate glycemic control owing to the increased insulin resistance resulting from nicotinic acid therapy. If carbohydrate tolerance deteriorates during nicotinic acid therapy, antidiabetic therapy should be instituted early and aggressively to restrain hyperglycemia from complicating the underlying metabolic syndrome or from producing a recrudescence of the hypertriglyceridemia or the low HDL cholesterol. In patients with overt hyperglycemia, thiazolidinediones are preferred for correction of hyperglycemia in patients with low HDL cholesterol. Nicotinic acid should be withheld until at least 6 months of antidiabetic therapy has been completed with thiazolidinediones, such as rosiglitazone or pioglitazone. Biguanides, such as metformin, may also be useful in improving insulin sensitivity and preventing weight gain in patients on nicotinic acid and thiazolidinediones. Combination therapy products of both rosiglitazone and metformin may be especially useful as initial treatment for new onset hyperglycemia in such patients, with secondary adverse eects of hyperglycemia as the consequence of nicotinic acid therapy.

Treatment of hypertension Numerous agents have been established as excellent rst-line therapies for hypertension in patients with diabetes and in nondiabetic patients with dyslipidemia. Ramipril, used in the HOPE Study, showed excellent antiatherogenic eects in diabetic patients with one additional coronary risk factor and in patients with coronary disease. Captopril and atenolol were equally eective for macrovascular risk reduction in patients with diabetes in the UKPDS. Calcium channel blockers such as felodipine (Plendil) also proved eective in diabetic patients in the HOT Trial. Finally, thiazide diuretics were found to be useful in the ALLHAT Study. Thus, a variety of agents can be chosen for patients with diabetes. Because most patients with type 2 diabetes evolve from a preexisting metabolic syndrome, the use of antihypertensive agents might be expected in patients with the metabolic syndrome, as they have been proven to be ecacious in patients with diabetes. Because endothelial dysfunction is an important part of the underlying insulin resistance state, which appears to be widely present in the metabolic syndrome, angiotensin-converting enzyme inhibitors and aldosterone receptor antagonists are useful in improving hypertension and

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relieving endothelial dysfunction in this population. Other agents may be equally ecacious in improving hypertension but may lack the ability to improve insulin resistance or endothelial dysfunction. These agents, including thiazide diuretics, b-blockers, cardioselective b-blockers, and potassium channel blockers, should be reserved for second and third line (or beyond) therapies. Part of the clinical issue in patients with diabetes is that the treatment target for antihypertensive therapy is a diastolic pressure less than 80 mm Hg. Attainment of such a target, which probably should extend to patients with prediabetic states, such as the metabolic syndrome, is the need for multiple antihypertensive agents, including an average of three, needed for diabetic patients in the United States, and at least two or more in the UKPDS. Thus, much of the discussion revolving around which one of a number of the foregoing antihypertensive agents should be considered the best antihypertensive agent in the metabolic syndrome or other prediabetic states is rendered moot and obviated by the fact that most of these agents will be required in combination to achieve the kinds of blood pressure targets now envisioned for such patients. One should therefore consider beginning with an angiotensin-converting enzyme or angiotensin II receptor blocker. A rapid dose escalation to include b-blockers, thiazide diuretics, calcium channel blockers, and other agents should be introduced to gain rapid control of the hypertensive state and improve endothelial dysfunction in these patients. Treatment of impaired carbohydrate tolerance The central diagnostic point of abnormal carbohydrate tolerance used in the NCEP 2001 Guidelines is a fasting glucose level greater than 110 mg/dL. This is known as impaired fasting glucose and may or may not be accompanied by impaired glucose tolerance (2-hour postchallenge glucose 140199 mg/dL). Although impaired glucose tolerance is clearly associated with the presence of underlying insulin resistance, impaired fasting glucose may or may not be associated with insulin resistance. It is, instead, more likely to be associated with declining b-cell function. There are no prospective randomized trials suggesting that pharmacologic therapy of impaired fasting glucose yields treatment benets either with regard to prevention of adverse coronary outcomes or the prevention of progression to type 2 diabetes. Nonetheless, it seems clear that pharmacologic modication may present a successful approach to this particular health problem because pharmacologic intervention with regard to impaired glucose tolerance has been demonstrated to be successful with regard to the prevention of type 2 diabetes. Studies such as the DPP and the TRIPOD studies have demonstrated ecacy of both metformin, in the former, and a thiazolidinediones in the latter, with regard to diabetes prevention. The thiazolidinediones therapy arm of the DPP study showed a striking, prolonged benet of thiazolidinediones therapy. It would therefore suggest

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that in patients failing benecial lifestyle modications or having insucient benet from lifestyle interventions, chemoprevention of diabetes may be warranted. On the other hand, it is completely unknown whether chemoprevention of diabetes with metformin or thiazolidinediones, or both, would have a benecial eect with regard to the adverse cardiovascular outcomes associated with the metabolic syndrome. Future studies to clarify this important point are clearly necessary.

Summary The metabolic syndrome is a collection of cardiovascular risk factors that denote a high-risk multifactorial adverse cardiovascular state, which is largely the result of obesity and the resulting insulin resistance. It is diagnosed by the presence of multiple risk factors, such as hypertriglyceridemia, low HDL cholesterol, hypertension, essential hypertension, abnormal fasting glucose levels, and abdominal or visceral obesity. This state also denotes a high-risk state for the evolution to type 2 diabetes. Treatment for the metabolic syndrome should be focused primarily on lifestyle modication, with reduction of the underlying obesity and insulin resistance. The treatment of individual coronary risk factors is clearly warranted in such patients because the metabolic syndrome represents a high-risk cardiovascular state equal to 20% or greater 10-year risk of coronary disease. In such patients, it may be possible that impaired glucose tolerance also exists. This diagnosis requires a glucose tolerance test to be performed. Chemoprevention of deterioration of impaired glucose tolerance to a future diabetic state has been successful with metformin or thiazolidinediones, as well as with aggressive lifestyle modication. Indeed, combination of both chemoprevention and lifestyle modication may prevent future cases of diabetes if instituted early in the course of diagnosis of impaired glucose tolerance. Whether such treatments benet the adverse cardiovascular outcomes remain to be decided.

References
[1] Executive summary of the Third Report of the National Cholesterol Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:248697. [2] Lebovitz H. Diabetes Reviews 1999. [3] Ridker PM, et al. Circulation 2003;107:3917. [4] Lakka HM, Laaksonen DE, Lakka TA, Niskanen LK, Kumpusalo E, Tuomilehto J, et al. The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men. JAMA 2002;288:270916. [5] United Kingdom Prospective Diabetes Study No. 34. Lancet 1998. [6] Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic syndrome among US adults: ndings from the third National Health and Nutrition Examination Survey. JAMA 2002; 287:3569.