S496 Vol. 5 (6A) n June 2005

ABSTRACT

This paper discusses the prevalence and clini-cal significance of the metabolic syndrome andconsiders the importance of lipid and lipoproteinabnormalities in the metabolic syndrome in con-ferring cardiovascular and metabolic risk. Themetabolic syndrome is a multiplex risk factor forcardiovascular and metabolic disease. Cardinalcomponents of the metabolic syndrome includeobesity (particularly abdominal obesity), dyslipi-demia, hypertension, and insulin resistance withor without glucose intolerance. The metabolic syn-drome affects approximately 47 million adultsand 2 million adolescents in the United States,and its prevalence is increasing. Early detectionand management of the components of the meta-bolic syndrome are critical for preventing ordelaying the development of type 2 diabetes mel-litus, heart disease, and other metabolic and car-diovascular complications. Changes in the qualityand quantity of specific blood lipids and lipopro-teins constitute one of the earliest manifestations ofthe metabolic syndrome. These early changes inlipoproteins are important because they can con-tribute to the development of cardiovascular andmetabolic disease and constitute a marker for themetabolic syndrome, thus affected individuals canbe identified for early intervention.(Adv Stud Med. 2005;5(6A):S496-S502)

Asubstantial minority of adults and adoles-cents in the United States are affected bythe metabolic syndrome, a constellation ofphysiologic abnormalities that are risk fac-

tors for type 2 diabetes mellitus and heart disease.1

Early detection and management of the componentsof the metabolic syndrome are critical for preventingor delaying the development of type 2 diabetes melli-tus, heart disease, and other metabolic and cardiovas-cular complications.1,2 This paper discusses theprevalence and clinical significance of the metabolicsyndrome and considers the importance of lipid andlipoprotein abnormalities in the metabolic syndromein conferring cardiovascular and metabolic risk.

THE METABOLIC SYNDROME

MANIFESTATIONS

In his seminal 1988 Banting lecture, Dr GeraldReaven identified a cluster of physiologic disturbancesthat he designated as syndrome X—a cluster of abnor-malities, including dyslipidemia, hypertension, andfasting hyperinsulinemia, that occurred in the contextof insulin resistance.3 Syndrome X, more commonlyknown today as the metabolic syndrome or the insulinresistance syndrome, is now established as a multiplexrisk factor for cardiovascular and metabolic disease.Cardinal components of the metabolic syndromeinclude obesity (particularly abdominal obesity), dys-lipidemia, hypertension, and insulin resistance with orwithout glucose intolerance (Table 1).2

PREVALENCE

The metabolic syndrome is highly prevalent in theUnited States, affecting approximately 47 millionadults. More than 1 in 5 adults (ie, 22%)—in a sam-ple of 8814 individuals in the United States drawnfrom the 1988 to 1994 National Health and NutritionExamination Survey III (NHANES III)—were deter-

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THE METABOLIC SYNDROME AS A RISK FACTOR FOR TYPE 2 DIABETESAND CARDIOVASCULAR DISEASE

—Roger S. Blumenthal, MD*

*Associate Professor of Medicine, Department ofMedicine-Cardiovascular, Johns Hopkins Ciccarone Center,Johns Hopkins University School of Medicine, Baltimore,Maryland.

Address correspondence to: Roger S. Blumenthal, MD,Associate Professor of Medicine, Department of Medicine–Cardiovascular, Johns Hopkins Ciccarone Center, JohnsHopkins University School of Medicine, 600 North WolfeStreet–Blalock 524 C, Baltimore, MD 21287. E-mail: rblument@jhmi.edu.

mined to have the metabolic syndrome as defined bythe criteria established by the National CholesterolEducation Program (NCEP) Expert Panel onDetection, Evaluation, and Treatment of High BloodCholesterol in Adults.4 In both men and women, theprevalence of the metabolic syndrome increased withage (Figure 1).4 Nearly 50% of those individuals 60years and older were determined to have the metabol-ic syndrome.

A recently published follow-up study conducted bythe Centers for Disease Control and Prevention(CDC) shows that the prevalence of the metabolicsyndrome is increasing among American adults, par-ticularly women.5 From 1994 to 2000, the age-adjust-ed prevalence of the metabolic syndrome increased by23.2% in adult women and by 2.2% in adult men inthe United States.

The metabolic syndrome affects more than 2 mil-lion adolescents in the United States.6 In a US popula-tion-based study, the overall prevalence of themetabolic syndrome among adolescents increasedfrom 4.2% in 1994 to 6.4% in 2000. According to thestudy, adolescent boys were more likely to develop themetabolic syndrome than were adolescent girls.Regardless of gender, those individuals who wereoverweight were more likely than normal-weightadolescents to develop the metabolic syndrome.Approximately 33% of overweight adolescents hadthe metabolic syndrome.

The rise in prevalence of the metabolic syndromecoincides with an increase in the incidence of obesityin all age groups in the United States. Obesity is acomponent of the metabolic syndrome and a patho-physiologic contributor to and risk factor for othermetabolic syndrome components.

CLINICAL SIGNIFICANCE

Research has established that the presence of onecomponent of the metabolic syndrome heightens therisk of having one or more of the other components.7

Furthermore, the degree of health risk associated withthe metabolic syndrome is directly related to the num-ber of components present.7 The metabolic syndrome isa substantial determinant of the risk of cardiovasculardisease and a harbinger of type 2 diabetes mellitus, com-plications of which include coronary heart disease, neu-ropathy, peripheral vascular disease, and retinopathy.

The degree to which the metabolic syndrome pre-dicts cardiovascular risk in women was assessed in the

Women’s Ischemia Syndrome Evaluation study,8 whichwas designed to determine the relative contributions ofobesity and the metabolic syndrome to coronary arterydisease. Women (n = 780) referred for a coronaryangiography to investigate suspected myocardialischemia were assessed for angiographic coronaryartery disease (defined as ≥50% stenosis) and a 3-yearrisk of major cardiac events (death, nonfatal myocar-dial infarction, stroke, or congestive heart failure). Theresults show that, although the metabolic syndromeand body mass index were significantly related, onlythe metabolic syndrome and not the presence of obe-sity per se predicted significant coronary artery diseaseor major adverse cardiovascular events. The researchers

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Table 1. Manifestations of the Metabolic Syndrome

• Obesity (particularly abdominal obesity)

• Atherogenic dyslipidemia

• Hypertension

• Insulin resistance with or without glucose intolerance

• Hyperglycemia

Data from JAMA. 2001;285:2486-2497.2

Figure 1. Age-Specific

Age-specific prevalence of the metabolic syndrome in a US population-based study.Data from Ford et al. JAMA. 2002;287:356-359.4

concluded that the metabolic syndrome, but not bodymass index, predicts cardiovascular risk in women.The goal of patient management, they suggested, isthe control of modifiable risk factors to prevent transi-tion to the metabolic syndrome.

Diabetes is considered a cardiovascular, in additionto a metabolic, disease because it increases the risk ofadverse cardiac events. Patients with type 2 diabetesmellitus are at a significantly increased risk of cardio-vascular morbidity and mortality as compared to thosepatients without diabetes:

• Patients with diabetes, as compared to individualswithout diabetes, are 3 to 5 times more likely todevelop cardiovascular disease.9

• Cardiovascular disease, the most common causeof death in diabetic adults, is responsible for 8 ofevery 10 deaths among those patients with dia-betes.10,11

• Patients with type 2 diabetes mellitus significantlyare more likely to experience fatal or nonfatal car-diovascular events than those patients without dia-betes. In fact, patients with diabetes and no historyof cardiovascular disease are as likely to experiencefatal or nonfatal cardiac events as those patientswithout diabetes and a history of myocardialinfarction.12 For example, in a study conducted inFinland (the East-West Study), the incidence offatal or nonfatal myocardial infarction over a 7-yearfollow-up period was 19% among nondiabetic sub-jects with a prior myocardial infarction and 20%among diabetic subjects with no prior myocardialinfarction (Figure 2).13 Patients with diabetes witha prior myocardial infarction were at extremelyhigh risk of a myocardial infarction: 45% experi-enced a fatal or nonfatal myocardial infarction dur-ing the 7-year follow-up period (Figure 2).13

Because diabetes confers a risk of cardiovasculardeath equivalent to that of established cardiovasculardisease, the NCEP designates diabetes as a coronaryheart disease risk-equivalent.2 Coronary heart diseaserisk-equivalents carry a risk of major coronary eventsequivalent to that of established coronary heart dis-ease. Similarly, the American Heart Associationemphasizes the link between diabetes and cardiovascu-lar disease: “Because of the aging of the populationand an increasing prevalence of obesity and sedentarylife habits in the United States, the prevalence of dia-betes is increasing. Thus, diabetes must take its place

alongside the other major risk factors as importantcauses of cardiovascular disease. In fact, from the pointof view of cardiovascular medicine, it may be appro-priate to say, diabetes is a cardiovascular disease.”14

Some evidence points to components of the meta-bolic syndrome, particularly insulin resistance, aspathophysiologic common denominators linking dia-betes with cardiovascular disease.15 For example, across-sectional analysis of the NHANES III datafound that the metabolic syndrome is significantlyassociated with self-reported history of myocardialinfarction or stroke. Insulin resistance, hypertension,and hypertriglyceridemia were independently associat-ed with increased risk of myocardial infarction orstroke.16 In a prospective study of more than 6000 par-ticipants from the NHANES II survey who wereobserved for an average of 13 years, an increased riskof coronary heart disease and cardiovascular mortalitywas demonstrated in individuals with the metabolicsyndrome. Individuals with the metabolic syndromeand diabetes had an even greater risk for coronaryheart disease, cardiovascular mortality, and total mor-tality (Figure 3).17

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Figure 2. Incidence of Myocardial Infarction

*P <.001 for diabetes versus no diabetes. †P <.001 for prior myocardial infarction versus no prior myocardial infarction. Incidence of myocardial infarction among patients with and without diabetesover a 7-year follow-up period.Data from Haffner et al. N Engl J Med. 1998;339:229-234.13

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The independent contribution of the metabolicsyndrome to cardiovascular risk has also beendemonstrated in populations outside the UnitedStates. The Kuopio Ischaemic Heart Disease RiskFactor Study, a population-based, prospective evalua-tion of more than 1200 Finnish men who at baselinedid not have cardiovascular disease or diabetes,showed that men with the metabolic syndrome, ascompared with those men without the metabolic syn-drome, were 3 times more likely to die of coronaryheart disease over a 9- to 14-year follow-up period.18

In the Botnia Study, which was conducted in Finlandand Sweden, the relationship between the presence ofthe metabolic syndrome and cardiovascular sequelaewas assessed in 3606 subjects over a median follow-up period of 6.9 years.19

The data show that those patients with the meta-bolic syndrome (regardless of whether they had a diag-nosis of type 2 diabetes mellitus) were significantlymore likely than those patients without the syndrometo experience cardiovascular morbidity and mortality.Individuals with the metabolic syndrome were 2.96times more likely to have coronary heart disease, 2.63times more likely to have had a myocardial infarctionprior to the study, 2.27 times more likely to have hada stroke during the study, and 1.81 times more likelyto die of cardiovascular causes. Of the patients withthe metabolic syndrome, 12% died of cardiovascularcauses as compared to 2.2% of those patients withoutthe metabolic syndrome (Figure 4).19

Recent studies have demonstrated an associationbetween the metabolic syndrome and subclinical ath-erosclerosis. Coronary artery calcification (CAC) isone measure of subclinical atherosclerosis and has thepotential ability to reflect the impact of all risk factorson the arterial wall. In most studies, the metabolic syn-drome predicted the severity of CAC independent ofthe Framingham risk score (FRS). Wong et al mea-sured the prevalence and quantity of CAC among1823 patients with diabetes, with metabolic syndromeand no diabetes, or with neither condition.20 Thewomen with diabetes had a prevalence of CAC of53%; those with metabolic syndrome and no diabetes,51%; and those women with neither condition, 38%(P <.001). The men with diabetes showed a 75%prevalence of CAC; those with metabolic syndromeand no diabetes, 59%; and those with neither condi-tion, 54% (P <.001).

A community-based study of 1120 asymptomatic

white adults in Rochester, Minnesota,21 found that themetabolic syndrome was associated with a 17%increase in CAC prevalence and, among those patientswho had detectable CAC, a 207% change in CACquantity (age and gender-adjusted, P <.001). Themetabolic syndrome remained positively and signifi-cantly associated with CAC after adjusting for the 10-year FRS (P <.001). The importance of the metabolicsyndrome in identifying subclinical atherosclerosis hasalso been demonstrated.22 In a cohort of 455 white

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Figure 4. Cardiovascular Deaths in Patients withor without the Metabolic Syndrome

Data from Isomaa et al. Diabetes Care. 2001;24:683-689.19

Figure 3. CHD, CVD, and Total Mortality Rates

CHD, CVD, and total mortality rates in individuals with and without themetabolic syndrome and diabetes.CHD = coronary heart disease; CVD = cardiovascular disease.Data from Malik et al. Circulation. 2004;110:1245-1250.17

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asymptomatic Brazilian men, the metabolic syndromeincreased the risk of any CAC (odds ratio [OR] 1.6;95% confidence interval [CI], 1.0–2.6) and CAChigher than the 75th percentile (OR 1.8; 95% CI,1.1–3.0). The metabolic syndrome was significantlyassociated with age-adjusted prevalence of CAC onlyin the low-risk group (FRS <10%; P = .01). Thesestudies indicate that the metabolic syndrome substan-tially influences atherosclerotic disease burden andmay be useful in risk assessment, especially for indi-viduals classified at low or intermediate risk by FRS.

LIPOPROTEINS AND THE METABOLIC SYNDROME

Changes in the quality and quantity of specific bloodlipids and lipoproteins constitute one of the earliest man-ifestations of the metabolic syndrome and can contributeto the development of cardiovascular and metabolic dis-ease. In addition, these early changes in lipoproteins con-stitute a marker for the metabolic syndrome, thusaffected patients can be identified for early intervention.

LIPOPROTEINS

Lipoproteins are large molecules composed oflipids (in the form of cholesterol, triglycerides, andphospholipids) and proteins (also known as apopro-teins).23 Lipoproteins typically are spherical and com-prise a core of water-insoluble components, includingcholesterols and triglycerides, and a shell of morewater-soluble components, including apoproteins andphospholipids. The lipid constituents of lipoproteinsare energy sources, a key component of all cellularmembranes, and also serve as the substrate for varioushormones including androgens, estrogens, and corti-costeroids. The protein constituents of lipoproteinsprovide structural stability to the lipoprotein mole-cule, serve as anchor points for interactions betweenlipoproteins and their targets, and contribute to theregulation of lipoprotein metabolism.

The main classes of lipoproteins include:• Chylomicrons. Chylomicrons are synthesized pre-

dominantly in the intestine and are responsible fortransporting dietary triglycerides and cholesterolfrom the intestines to the liver and other tissues.

• Very low-density lipoprotein (VLDL). VLDLs aresynthesized primarily in the liver. Their mainlipid constituent is liver triglycerides. VLDLs aresynthesized from triglycerides by the action of an enzyme known as lipoprotein lipase.

• Intermediate-density lipoprotein (IDL). IDLs aresynthesized from VLDL by the action of lipopro-tein lipase in various tissues and organs, includingthe blood. The main lipid constituents of IDL arecholesterols and triglycerides.

• Low-density lipoprotein (LDL). LDLs are synthe-sized from IDL (which come from VLDL) in var-ious organs and tissues, including the blood.Cholesterols are their primary lipid constituent.

• High-density lipoprotein (HDL). HDLs are synthe-sized in the intestine, liver, and plasma via complex biochemical pathways. The primary lipid con-stituents of HDL are cholesterols.

Lipoproteins vary in size and density.24 HDL parti-cles are the smallest, most dense lipoproteins; VLDLsand chylomicrons are the largest, least dense lipopro-teins. The size and density of lipoprotein particles isdetermined by the amount of cholesterol and triglyc-eride contained within their lipid cores.24 For example,the core composition of LDLs, which are ultimatelysynthesized from triglyceride-rich VLDL, is deter-mined largely by plasma triglyceride levels. Elevation ofplasma triglyceride levels favors a biochemical reaction,whereby VLDLs exchange their triglyceride moleculesfor cholesterol molecules contained in the core of theLDL. This reaction results in a cholesterol-depleted,triglyceride-rich LDL. In this form, the LDL is espe-cially vulnerable to the activity of hepatic lipase, whichtransforms the large, cholesterol-depleted LDL to asmaller, denser LDL particle. This reaction is impor-tant in the pathogenesis of cardiovascular disease:small, dense LDL particles are more conducive to ath-erosclerosis than are larger, less dense LDL particles.25,26

The metabolic syndrome is associated with a char-acteristic triad of lipoprotein abnormalities:

• Low HDL levels,• High triglyceride/VLDL levels, and• Elevations in small, dense LDL particles.27

These lipoprotein abnormalities are brought aboutlargely by an excess of blood levels of free fatty acidsfrom which lipoproteins are synthesized. These eleva-tions in free fatty acid levels are attributed partly to theinability of insulin to stimulate uptake and the use offree fatty acids in insulin-resistant tissues. For example,skeletal muscle, which normally uses free fatty acidsfor energy, cannot in an insulin-resistant state use freefatty acids circulating in the bloodstream. As a result,

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levels of free fatty acids increase in the liver, whichincreases VLDL production in response.28

The lipoprotein profile characteristic of the meta-bolic syndrome was defined in part on the basis of datafrom the Insulin Resistance Atherosclerosis Study, alarge multicenter study of insulin resistance and car-diovascular disease in African Americans, Hispanics,and non-Hispanic whites.29,30 Among 479 patientswith type 2 diabetes mellitus, the patients who wereinsulin-resistant (n = 442), as compared with thepatients who were insulin-sensitive (n = 37), had sig-nificantly lower levels of HDL cholesterol, which isvasculoprotective, and significantly higher levels ofVLDL cholesterol and triglycerides (Table 2).29

Furthermore, mean LDL particle size was significantlysmaller among patients who were insulin-resistant ascompared to patients who were insulin-sensitive(256.9 angstroms vs 260.5 angstroms). Neither totalcholesterol levels nor LDL cholesterol levels differedbetween the 2 groups of patients.

In an analysis of data from a larger sample of par-ticipants (n = 1549) in the Insulin ResistanceAtherosclerosis Study, LDL particle size was correlatedstrongly and positively with the degree of insulin sen-sitivity (r = 0.21; P <.0001).30 Thus, the smaller theLDL particle size, the less the insulin sensitivity (andthe greater the insulin resistance). LDL particle sizewas related inversely to fasting insulin levels—thesmaller the LDL particle size, the greater the fastinginsulin level. Unlike the smaller sample described ear-lier in this section, this sample of patients includeddiabetic and nondiabetic subjects to assess the rela-tionships between cardiovascular risk factors andinsulin resistance across a range of insulin sensitivities.

The lipoprotein profile characteristic of the meta-bolic syndrome also occurs in diabetes, but abnormal-ities in lipoproteins predate the development ofdiabetes by years. In an early analysis of data from theSan Antonio Heart Study, the cardiovascular status of614 Mexican-American men who were nondiabetic atbaseline was compared to those men who developedtype 2 diabetes mellitus and those who remained non-diabetic over an 8-year follow-up period.31 The resultsshow that those men who developed type 2 diabetesmellitus had higher baseline levels of total cholesterol,LDL cholesterol, and triglycerides and lower HDLcholesterol levels than those men who did not developdiabetes. The lipid abnormalities were observed evenin prediabetic patients who did not show signs of

impaired glucose tolerance, an early sign of type 2 dia-betes mellitus. Those men who developed type 2 dia-betes mellitus also showed baseline abnormalities inbody weight, blood pressure levels, blood glucose val-ues, and blood insulin values.

These data show that the onset of lipoproteinabnormalities in insulin resistance and type 2 diabetesmellitus occurs substantially earlier than other mani-festations of these conditions. Lipoprotein abnormali-ties in insulin resistance predate the onset of type 2diabetes mellitus, in addition to diabetic macrovascu-lar and microvascular complications. These earlychanges in lipoproteins undoubtedly contribute to thedevelopment of cardiovascular disease in patients withthe metabolic syndrome. The early changes in lipopro-teins also constitute a marker for adverse cardiovascu-lar and metabolic outcomes, thus affected individualscan be identified for early intervention.

Strategies for recognizing and managing dyslipi-demia and other components of the metabolic syn-drome in clinical practice are explored later in thismonograph in the article by Dr Michael H. Davidson.

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Table 2. Cardiovascular Risk Factors as a Function of Insulin Sensitivity in Patients with Type 2 Diabetes

Shaded variables designate statistically significant differences (P <.05)between insulin-resistant patients and insulin-sensitive patients.HDL = high-density lipoprotein; LDL = low-density lipoprotein; VLDL =very low-density lipoprotein.Data from Haffner et al. Diabetes Care. 1999;22:562-568.29

Insulin-Resistant Insulin-SensitiveCardiovascular Patients Patients

Risk Factor (n = 442) (n = 27)

Total cholesterol, mg/dL 215.2 220.2

LDL cholesterol, mg/dL 140.4 145.7

HDL cholesterol, mg/dL 39.5 45.3

VLDL cholesterol, mg/dL 26.5 20.5

Total triglyceride, mg/dL 166 133

VLDL triglyceride, mg/dL 122.4 87.2

LDL size, angstroms 256.9 260.5

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