Diagnosis and Treatment of Metabolic Syndrome in Menopausal Women

8/8/2019 Diagnosis and Treatment of Metabolic Syndrome in Menopausal Women

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16 MENOPAUSEMANAGEMENT

The Controversy

A diagnosis of metabolic syndromehas been the subject of controversy.

This controversy has several facets.4-7

There are multiple definitions ofmetabolic syndrome, which has ledto some confusion as to whether ornot the syndrome describes an actualbiological entity or whether it issimply a construct. Small changes in

the cut points used in the definitionof metabolic syndrome will likelyimpact its specificity and sensitivityin the prediction of cardiovascularrisk. Some have questioned whetheror not the risk of atheroscleroticcardiovascular disease (ASCVD) as-sociated with metabolic syndrome isgreater than that of the sum of itsrisk factors. However, the risk of

ASCVD rises geometrically rather

than linearly with the addition ofmetabolic syndrome risk factors,and the increased incidence of type2 diabetes mellitus (T2DM) addi-tionally increases long-term risk.3

There is also controversy concerningthe clinical utility of the metabolicsyndrome, as no prospective trials

yet exist demonstrating that the di-agnosis of the metabolic syndromeand implementation of specific ther-

apeutic regimens would affect the

Metabolic syndrome is a disorder of combined lipid and

glucose metabolism in a genetically susceptible individual

with sufficient visceral adiposity to provoke adipose tissue

dysfunction. This adipose tissue dysfunction also results in

hypertension, glucose intolerance, and a proinflammatory,

prothrombotic state. Physiologic features of menopause

such as decreased insulin sensitivity, estrogen deficiency, shiftto an android body habitus and weight gain, as well as lack of

physical activitycontribute to the development and risk of

metabolic syndrome in menopause. Age itself remains a

predominant risk factor for metabolic syndrome.

Endocrinologist Gerald Reaven, who helped to draw attention

to the metabolic syndrome concept, is quoted as having said,

All obese people are not created equalinsulin resistance is

the major determinant of cardiovascular disease in overweight/obese individuals.1 Previously thought of as a pre-diabetes

syndrome, metabolic syndrome is now more properly viewed as

a pre-coronary syndrome because of the associated increased

risk of cardiovascular events. Cardiovascular disease remains

the leading cause of morbidity and mortality among menopausal

women, and despite preventive efforts we have been less

successful in reducing this risk in women than in men.2,3

Early and accurate risk prediction and aggressive prevention

would seem to be what is needed.

Diagnosis and Treatmentof Metabolic Syndromein Menopausal WomenGregory S. Pokrywka, MD, FACP

(continued on page 17)


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NOVEMBER/DECEMBER2007 17

morbidity or mortality from ASCVDor from T2DM. (Post hocanalysis doesreveal that patients with metabolicsyndrome derive incremental benefitfrom intensified statin therapy8).

Regardless of whether metabolicsyndrome is ultimately determined

to be a distinct biological entity, adiagnosis serves to identify patientsat a two- to three-fold increased riskfor ASCVD, who might benefitfrom more intensive lifestyle and,possibly, pharmacologic therapy.9

The predictive value of metabolicsyndrome has generally not beenshown it to be superior to the Fram-ingham Risk Score (FRS) in delin-eating short-term (10-year) ASCVD

risk.

10

However, the diagnosis ofmetabolic syndrome remains astrong predictor oflong-term coro-nary heart disease (CHD) risk andidentifies potentially high-risk pa-tients, especially in women over 55

years of age. A diagnosis of meta-bolic syndrome identifies those atrisk for T2DM and stroke; the FRSdoes not. The FRS may, in fact, se-riously underestimate lifetime car-

diovascular risk in women.

11

Thus, clinicians face a dilemmawith regard to accurate risk predic-tion and treatment, and may need toresort to additional tools, such asimaging studies, biomarkers and ad-

vanced lipoprotein analysis to aug-ment the FRS. However, validationof cardiac imaging and biomarkersas tools to screen for long-term riskin insulin-resistant states awaits

prospective trial data.12

The diag-nosis of metabolic syndrome ex-

tends the concept of CVD risk andshould not be viewed as a competi-tor to the FRS tool, but rather asan enhancement.4

Metabolic Syndrome in Women:

What Studies Show

Although no studies have specifi-cally looked at menopausal women,multiple studies (the San AntonioHeart Study, the Atherosclerosis

Risk in Communities study, theHoorn study, and the Health, Agingand Body Composition study) havesuggested that the metabolic syn-drome may be more predictive ofCHD events in women than inmen.13-15A recent, 10-year, prospec-tive multicenter trial in China of ap-proximately 30,000 subjects showedthat metabolic syndrome signifi-cantly increased CVD risk com-

pared with patients who do nothave metabolic syndrome but whodo have hyperglycemia. The riskof CVD in this population was

largely attributable to the accom-panying metabolic abnormalitiesof metabolic syndrome rather thanthe hyperglycemia alone.16

Metabolic syndrome had an ad-verse impact on CVD health andmortality in the Botnia Study,17 aprospective 7-year trial with morethan 3,000 patients (average age of

women, >50 years). There was a 2-to 3-fold relative risk increase in

total mortality, CHD mortality,CHD incidence, myocardial infarc-tion and stroke (Figure 1).17

The recently completed Monitor-ing of Trends and Determinants inCardiovascular Disease trial18 is aprospective Danish population-based study of 2,493 men and

women, ages 41 to 72 years, withoutmajor CVD at baseline. Over a me-dian follow-up of 9.4 years, the rel-

ative risk (RR) of cardiovascular endpoints (CV death, nonfatal ischemicheart disease and nonfatal stroke,adjusted for age, gender, smoking

Figure 1. Metabolic syndrome has a negative impact on CV healthand mortality.17

Diagnosis and Treatment of Metabolic

Syndrome in Menopausal Women

(continued from page 16)


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and low-density lipoprotein choles-terol [LDL-C]) was increased by1.56 (95% confidence interval [CI],1.12 to 2.17).18 The authors con-cluded that both insulin resistanceand metabolic syndrome, as definedby the National Cholesterol Educa-tion Program Adult Treatment Panel(NCEP-ATP III), independentlypredict cardiovascular disease.

A new meta-analysis of 40 studies

varying in length from 2 to 16 yearsin 172,573 individuals, using end-points of new heart disease events ordeath, showed metabolic syndromehad an RR of 1.78 (95% CI, 1.58-2.00). The association was strongerin women than in men (RR, 2.63 vs.1.98, P= 0.09.) Multivariate analy-sis adjusting for the individual com-ponents of metabolic syndromedemonstrated cardiovascular risk

beyond that associated with its in-dividual risk factors (RR, 1.54; 95%CI, 1.32-1.79).19

The Enlarged Waist/ElevatedTriglycerides (EWET) trial was thefirst long-term prospective study ofmetabolic syndrome risk factors ina community-based, menopausal-specific population.20 Rather thaninvestigating all the factors ofmetabolic syndrome as defined by

the American Heart Association/National Heart, Lung, and BloodInstitute (AHA/NHLBI), EWETused only the two parameters of en-larged waist size (over 35 inches)and elevated triglycerides (128mg/dL) in estimating cardiovascularmortality in 557 menopausal womenages 48 to 76, who were followedprospectively for 8.5 years. Mortality

was increased almost 5-fold by the

presence of EWET, and metabolicsyndrome risk factors other than

elevated triglycerides and elevatedwaist added little to risk prediction inthis model. The authors concludedthat the presence of EWET may bethe best indicator of cardiovascularrisk in menopausal women. Newstudies confirm that both fastingand nonfasting triglycerides are im-portant independent risk factors forcardiovascular events.21,22

The Role of Risk Factors

The incidence of new-onset T2DM,a CHD relative risk equivalent inthe NCEP guidelines, correlates

with the number of characteristics,or risk factors, of metabolic syn-drome. Patients with four or five riskfactors for metabolic syndrome havea 24-fold greater risk for T2DMcompared with patients who haveno risk factors.23 There is also evi-

dence that CHD risk increases withthe number of components of meta-bolic syndrome,24 as does ischemicstroke risk (two to three times in-creased relative risk).25 Analysis ofthe Framingham Offspring Study(1,774 women, average age >50 years)revealed significant increases in totalCVD and hard CVD outcomes (my-ocardial infarction or CHD death)

with the diagnosis of metabolic

syndrome.

24

The increases in theseevents were steeper in women than inmen, which correlated with the num-ber of metabolic syndrome risk fac-tors present (Table 1). Increases inrelative risk of T2DM were greaterthan increases in CVD events.

Diagnostic Criteria

The AHA/NHLBI diagnostic crite-ria for metabolic syndrome (Table 2)

are well known and are discussed indetail elsewhere.9These criteria can

be adapted for multiethnic popula-tions; for example, by reducing thecriterion for elevated waist circum-ference in South Asian women. Theincidence of the metabolic syndromeincreases with age; the prevalence ofmetabolic syndrome increased fromapproximately 7% among partici-pants between ages 20 and 29 to ap-proximately 43% for patients over60 years of age.26The prevalence of

metabolic syndrome differs withrace, with the age-adjusted preva-lence being highest among Mexican-

American individuals and lowestamong African-Americans and peo-ple of other racial categories. Themost recent data suggest that ap-proximately 50 million Americanshave metabolic syndrome.

Pathophysiology

The pathophysiology of metabolicsyndrome involves dysfunctionaladipocytes (adiposopathy). Adipo-sopathy is defined as pathologicadipose tissue dysfunction that maybe initiated and/or exacerbated byfat accumulation in genetically sus-ceptible patients.27 Increased vis-ceral adipose tissue dysfunctionoften correlates with the amount of

visceral adipose tissue and also with

an increased number of metabolicsyndrome components (score).The Womens Ischemia SyndromeEvaluation (WISE) study demon-strated the importance of where amenopausal womans body fat ismainly located.28The odds ratio ofsignificant coronary artery diseaseby angiography was related to thepresence or absence of metabolicsyndrome at any weight, even in the

absence of obesity. The relative risk ofmortality and CVD events was more


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closely related to metabolic syndromethan to body mass index (BMI).

Many patients have a geneticallyimpaired inability to make new adi-pose cells (adipogenesis) under con-ditions of positive caloric balance,resulting in adipose cell hypertro-phy and resultant hypoxic-inducedstress. These stressed adipocytesrelease pathologic adipocytokines,lipotoxic nonesterified free fatty

acids (NEFAs) and other pro-inflammatory factors that promoteendothelial dysfunction, increaseinsulin resistance and increase CVDrisk. Adiposopathy reduces the ben-eficial cytokine adiponectin, whichhas a number of anti-atheroscleroticeffects on the vasculature, promotesinsulin sensitivity, and has beenstrongly linked to reduction of car-diovascular risk.27

Clinical diagnosis of metabolicsyndrome is an excellent way toidentify the increased CVD risk ofadiposopathy and the associatedatherogenic triada cluster of non-traditional risk factors that confersa dramatic increase in CVD risk: hyperinsulinemia, small, dense LDL particles, and an elevated number of athero-

genic ApoB lipoprotein particles.

The risk of ischemic heart dis-ease is differentially increased ac-cording to the cumulative numberof traditional and nontraditionalrisk factors. The presence of theatherogenic triad confers an almost21-fold increased relative risk overpatients in a similar quartile of tra-ditional risk factors.29

The NCEP-ATP III 2004 ad-

dendum guidelines recommendclassification of risk according to

the presence of major risk factors(family history of premature CVD,low high-density lipoprotein cho-lesterol [HDL-C], age, smokinghistory and hypertension) and theFRS. Intensity of treatment of plasmalipid concentrations is directly pro-portional to the risk predicted by

this algorithm.30

However, there aredistinct advantages in shifting the

emphasis from a lipid-concentra-tion risk management strategy toa lipoprotein-concentration riskmanagement strategy.31,32Although

we have traditionally used plasmalipid (cholesterol and triglyceride)concentrations as determined bythe standard lipid panel (total-

cholesterol, LDL-C, HDL-C, verylow-density lipoprotein cholesterol

Table 2. National Cholesterol Education Program9

Adult Treatment Panel III (NCEP-ATP III)

Metabolic Syndrome diagnosis suggested by the presence of 3 or more of the

following features:

1. Waist >35 inches in women ( >31 inches in South Asians)

2. Triglycerides >150 mg/dL (or on drug treatment with a fibrate or niacin for elevated TG)

3. HDL-C 100 mg/dL (or on drug treatment for elevated glucose)

TG = triglycerides; DBP = diastolic blood pressure; HDL-C = high-density lipoprotein cholesterol;

SBP = systolic blood pressure

EventNo. of Metabolic

Syndrome Risk Factors

Age-Adjusted Relative Risk (95% CI)

Men Women

CVD 0 Referent Referent

12 1.48 (0.693.16) 3.39 (1.318.81)

3 3.99 (1.898.41) 5.95 (2.2016.11)

Hard CVD 0 Referent Referent

12 0.98 (0.362.67) 3.77 (0.4531.28)

3 2.55 (0.966.79) 7.21 (0.8164.37)

Total CHD 0 Referent Referent

12 1.24 (0.542.83) 3.29 (0.9511.34)

3 3.01 (1.336.83) 3.96 (1.0215.38)

T2DM 0 Referent Referent

12 4.16 (0.9817.64) 6.10 (1.8520.10)

3 23.83 (5.8098.01) 29.69 (9.1096.85)

Table 1. Metabolic Syndrome Components and CV RiskA Greater Number of Metabolic Syndrome Components Leads to Greater Risk

for CV Events: Framingham Offspring Study 8-Year Follow-Up

CVD = cardiovascular disease; CHD = coronary heart disease; T2DM = type 2 diabetes mellitus

Wilson PWF, et al. Circulation 2005;112:3066-3072. Reprinted with permission of Lippincott Williams & Wilkins.


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[VLDL-C] and triglycerides), it isnow well established from epidemi-ologic and clinical trials that, infact, CVD risk tracks more closely

with plasma lipoprotein concentra-tions.31,32 This is especially true ininsulin-resistant populations.

Plasma lipoprotein concentra-tions are better than any of theplasma cholesterol indices at assess-ing residual risk patients experience

after theyve begun treatment.Apolipoprotein B is a surface pro-tein component of atherogeniclipoproteins (LDL, VLDL, inter-mediate density lipoproteins andremnant particles). Each of theselipoproteins contains a single mole-cule of ApoB. Cardiovascular risk isincreased by an increased ApoB par-ticle concentration. ApoB determi-nation is simple, standardized and

directly measured (unlike LDL-C,which is a calculated value). An eas-ily calculated non-HDL-C value(total-cholesterol concentration mi-nus the HDL-cholesterol concen-tration) serves as an alternative

validated tool for assessment of riskfrom all circulating ApoB parti-cles.33 LDL particle concentration(LDL-P) determined by nuclearmagnetic resonance imaging is an

alternative method for determiningplasma lipoprotein concentration-associated risk.34

The lipoprotein abnormalities ofmetabolic syndrome are an exces-sive number of atherogenic ApoBlipoprotein particles, accompaniedby reduced numbers, as well as dys-function, of HDL particles (Figure2). Under conditions of adiposopa-thy, visceral fat cells are unable to

properly control and store NEFAs.35

When the liver is confronted with an

excessive concentration of NEFAs(and/or when augmented by an ex-cessive simple carbohydrate diet),triglyceride synthesis is initiated.

The liver is not adapted to handlean excessive load of triglycerides.Hypertriglyceridemic situations likemetabolic syndrome lead to an over-production of large triglyceride-rich

ApoB-containing VLDLs, whichare associated with fasting and

postprandial hypertriglyceridemia.Triglyceride-rich VLDLs, them-selves highly atherogenic, are subjectto altered lipolysis, which createssmaller VLDL particles (remnants)and small, dense LDL and HDLparticles. This process results in lowHDL-C and HDL particle counts(HDL-P). Patients with small LDLparticles typically have high LDL-P(ApoB) concentrations.31 Since many

metabolic syndrome patients withsmall LDL particles have lowHDL-C, they will often have ab-normalities of non-HDL-C, total

cholesterol (TC)/HDL-C and tri-glycerides (TG)/HDL-C ( >4:1 isabnormal) ratios.36The scenario ofnormal LDL-C associated with el-evated non-HDL-C, or abnormal

TC/HDL-C or TG/HDL-C ratioscan be used to identify elevated

ApoB and likely contributes to theresidual CV risk so common inthese patients.34,37

Low HDL-C is the most com-

mon abnormality associated withCVD events in the Framinghamstudy and is often associated withinsulin-resistant syndromes likemetabolic syndrome. Low HDL-Cis often associated with increasednumbers of atherogenic VLDLremnants and small LDL particles.

Also contributing to the risk is thealtered functionality of HDL parti-cles common in proinflammatory

states like metabolic syndrome andT2DM. Inflammatory proteins ren-der HDL particles less efficaciousat performing macrophage reverse

Figure 2. Lipoprotein abnormalities of insulin resistance/adiposopathy.


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cholesterol transport, and deliveringanti-inflammatory, anticoagulantand profibrinolytic proteins to areasof arterial plaque. It is becoming ev-ident that the new term HDLfunctionality is likely very impor-tant in atherogenesis. Therapeuti-cally improving HDL functionalitymay be more important than in-creasing HDL-C.38,39

Treatment

The 2007 AHA guidelines for theprevention of cardiovascular diseaserisk in women emphasize the as-sessment of lifetime risk in womeninstead of the previous emphasisupon assessment ofshort-term risk.10

The Framingham risk paradigm isexcellent at assessing 10-year risk in

women, but we now have substantialdata showing that even the presence

of one major cardiovascular risk fac-tor in a woman over 50 years of age will increase her lifetime risk forcardiovascular disease dramatically.

There is also evidence that there isa broad heterogeneity of risk pres-ent in women with a given FRS. Ahigh-risk FRS (>20%) identifies

women at high risk, but a lower scoreis not sufficient to ensure that an indi-vidual woman is at low risk. The com-

bined use of metabolic syndromediagnosis with a lipoprotein particle-based treatment approach provides arational approach to management ofrisk in menopausal women.

Therapeutic lifestyle change. Thegoals of treatment in metabolic syn-drome are to simultaneously de-crease the instance of CHD eventsand to prevent or delay the devel-opment of T2DM. The cornerstone

of treatment is therapeutic lifestylechange directed at improving adi-

pose tissue dysfunction, not neces-sarily reduction in adipose tissuemass. The establishment of a meta-bolic syndrome clinic in the health-care providers office to specificallytarget and treat metabolic syndromethrough therapeutic lifestyle changeis a promising approach, as intensivelifestyle modification has beenshown to improve components ofmetabolic syndrome.40-42 Thera-

peutic lifestyle change in metabolicsyndrome consists of promotion ofdaily moderate-intensity exercise,modest weight reduction, a healthylow glycemic index or Mediter-ranean-style diet and increased con-sumption of omega-3 fatty acids(Table 3). Modest weight reduction(5-10%) and walking 150-180min/week improves many of thephysiologic abnormalities of meta-

bolic syndrome and slows the pro-gression to T2DM. Self-monitoringof parameters such as food intake,body weight and exercise level iscritical for success. Exercise man-agement should consist of at least 30minutes of moderate-to-vigorous

physical activity on most days ofthe week. If this activity is weight-bearing, the dual benefit of potentialprevention of menopausal osteo-porosis can also be accomplished.

The use of inexpensive pedometersto set and track goals for the simplestform of modest-intensity exercise

walkingis practical and effective;more than 10,000 steps/day is con-sidered an active lifestyle. An ex-

ercise prescription of adding >1,000kcal/week of exercise (~20,000-25,000 steps/week) consisting ofmoderate-intensity walking is rec-ommended.43 Patients should be re-minded that regardless of any weightloss achieved, physical activity is in-sulin sensitizing and is of cardiores-piratory and psychological value.44

Goals for an individualized dietinclude a reasonable reduction in

weight of 7% to 10% over 1 year,with the eventual goal of obtainingideal body weight. This is achievedby the initiation of reduced caloricintake and reduced consumption ofsimple carbohydrates, under the su-pervision of a clinical nutritionist if

Table 3. Implementing Therapeutic Lifestyle Changes

Specific contract with patient for goals and self-monitoring.

Exercise at least 30 minutes of moderate to vigorous physical activity on mostdays of the week. Using pedometer, walking >10,000 steps/day is desirable.

Diet reduction of weight by 7-10% over 1 year with reduced caloric intake and

reduced consumption of simple carbohydrates (low glycemic index diet). Womenshould consume a diet rich in fruits and vegetables; whole-grain, high-fiber foods;limited intake of saturated fat to 10% of energy (if possible to 7%); cholesterol to300 mg/d; no more than 1 alcoholic drink per day; consumption of trans-fatty acids(FA) should be as low as possible.

Increased omega-3 FA consumption (~850-1000 mg EPA + DHA / day)

Women should not smoke and should avoid environmental tobacco smoke.

EPA=eicosapentaenoic acid; DHA=docosahexaenoic acid


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possible. Attainment of ideal bodyweight is obviously difficult in thispopulation, but even modest weightloss has been associated with labo-ratory improvement and clinical riskreduction.40 Increased soluble fiberintake and reduction of saturatedand trans fatty acid intake are to berecommended as well. Plant stanolesters significantly lower LDL-Cand are available in various func-

tional foods.

45

Increased omega-3fatty acid consumption (approxi-mately 1,000 mg of eicosapentaenoicacid [EPA] and docosahexaenoicacid [DHA] per day) reduces risk in

women with CVD, and it is reason-able to extend this treatment tohigh-risk patients such as those withmetabolic syndrome.

Pharmacologic treatment. Pharma-cologic treatment of cardiovascular

risk in metabolic syndrome is basedon the assessment and treatment ofrisk using an atherogenic particle-based approach.46 Aggressive treat-ment is safe, effective and well

within the scope of practice of allprimary care providers,47 and neednot be left to internists and cardiol-ogists once risk is identified.

An aggressive goal is to reducethe atherogenic ApoB particle count

to physiologic levels associated withlow CVD risk (Table 4). Statindrugs inhibit cholesterol synthesis inalmost all cells, although the liver isthe organ that clears ApoB parti-cles. The largest body of evidencefor pharmacologic risk reduction ininsulin-resistant patients exists forstatins. First-line pharmacologicstrategy to reduce ApoB-containingparticles would be appropriately

dosed statin therapy. A complemen-tary strategy would be to reduce the

number of circulating triglyceride-rich VLDL particles driving thelipoprotein abnormalities of meta-bolic syndrome, by either reducingtheir production in the liver or in-creasing their catabolism, with fi-brates, niacin or high-dose omega-3fatty acids. The fibrates regulate

multiple genes involved with glucoseand fatty acid metabolism, lipopro-tein synthesis and catabolism, and

vascular inflammation. They de-crease the hepatic production oftriglycerides, increase the catabolismof triglyceride-rich lipoproteins andincrease the synthesis and function-

Table 4. Metabolic Syndrome Pharmacologic Treatment 9,11,31,32

Assessment and treatment of risk using an atherogenic particle-basedapproach (instead of a traditional lipid-based approach)

Primary goal: reduce atherogenic ApoB particles to physiologic levels

Lifestyle approaches should be encouraged to reach the following optimal lipid levels:

LDL-C < 100 mg/dL

HDL-C > 50 mg/dL

TG < 150 mg/dL

Non HDL-C < 130 mg/dL

Framingham Risk Scoring should be done to stratify absolute 10-year risk of ASCVD.

Goals of treatment for those atmoderately high risk

(

2 risk major risk factors, with10-20% risk) and high-risk patients (known CVD or T2DM or CHD equivalent*):

Non-HDL-C < 130 mg/dL OR ApoB < 80 mg/dL OR NMR LDL-P < 1000 nMol/L

Very high-risk women (established CVD plus any of the following: MetSyn, multiplemajor risk factors, severe and poorly controlled risk factors, T2DM) have lower goals:

Non-HDL-C < 100 mg/dL OR ApoB < 60 mg/dL OR NMR LDL-P < 1000 nMol/L

Statin is first-line Rx to reduce ApoB particles.

If not at non-HDL-C, ApoB or LDL-P goal, add fenofibrate. Ezetimibe or bile acidsequestrant or Rx extended-release niacin can be added if goal not attained.

Aggressive hypertension control. Optimal BP < 120/80. Treat to < 130/80, withACE inhibitors/ARBs preferred, with thiazide diuretics next if needed.

Management of hyperglycemia (FBS > 100 mg/dL ) with metformin, especiallywith an abnormal glucose tolerance test.

81- to 162-mg enteric-coated aspirin, unless contraindicated.

Weight-loss medications or bariatric surgery may be helpful in some patients.

*CHD equivalent = known peripheral arterial disease, abdominal aortic aneurysm, carotidartery disease, chronic renal disease (creatinine > 1.2 mg/dL)

LDL-C = low-density lipoprotein cholesterol; HDL-C= high-density lipoprotein cholesterol;TG = triglycerides; ASCVD = atherosclerotic cardiovascular disease; T2DM = type 2 diabetes mellitus;CHD = coronary heart disease; Apo-B = apolipoprotein B; NMR = nuclear magnetic resonance;MetSyn = metabolic syndrome; LDL-P = LDL particle concentration; FBS = fasting blood sugar


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ality of HDL particles.48 Trial datareveal that fibrates are significantlymore efficacious in insulin-resistantpatients. In the Fenofibrate Inter-

vention and Event Lowering inDiabetes (FIELD) trial, fenofibratedemonstrated a trend toward CVDrisk reduction (nonsignificant ab-solute risk reduction) in women

with T2DM, as well as reduction ofmicrovascular endpoints, such as the

need for laser-photocoagulationretinal therapy, microalbuminuriaand peripheral amputations.49 Con-sistent with other fibrate trials,FIELD patients with dyslipidemia(triglycerides >150 mg/dL and HDL


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concerns.57Aggressive hypertensioncontrol (treat to 10% 10-yearrisk of CVD on the FRS shouldreceive low-dose aspirin therapy(81-162 mg enteric-coated aspirin),unless contraindicated. The man-agement of insulin-resistant hyper-glycemia (especially impaired glucosetolerance) itself can be augmented

with the addition of pharmacologictherapy with metformin. Metforminadditionally may provoke weight loss

or stabilization, and has been shownto reduce mortality in T2DM59 andthe progression to T2DM. The useof thiazolinediones as insulin-sensitizing agents for risk reductionand T2DM prevention has been ad-

vocated.60 A recent meta-analysissuggested increased CVD risk withthe thiazolinedione rosiglitazone,61

although this is controversial.62Therole of other hypoglycemic and

insulin-resistance-reducing drugs,such as acarbose, exenatide andsitagliptin, is unclear.

Summary and Conclusions

The diagnosis of metabolic syn-drome helps to identify menopausalpatients at increased long-term riskfor ASCVD, T2DM and ischemicstroke. Despite the fact that thesepatients may have only modest

elevations of individual risk factors,such as high blood pressure and

elevated lipids, the presence ofmetabolic syndrome helps identifypatients with the adverse physiologicstate of adiposopathy, and its accom-panying pathologic combination ofabnormal lipoproteins, cytokines andpro-inflammatory factors. These pa-tients might benefit from more in-tensive therapeutic lifestyle changesand pharmacologic therapy, targetedspecifically at improving their un-

derlying adiposopathy and increasedatherogenic ApoB lipoproteins, andat prevention of T2DM. The patienthand-out on pages 27 and 28 willserve as a valuable tool for makingpatients active participants in achiev-ing these goals.

Gregory S. Pokrywka, MD, FACP, is Assis-

tant Professor of Medicine at Johns Hop-

kins University School of Medicine,

Baltimore, MD; and Director of the Balti-more Lipid Center, Towson, MD.

Dr. Pokrywka participates in the Speakers

Bureaus for AstraZeneca PharmaceuticalsLP, Abbott Laboratories, Sanofi-Aventis,

Oscient, LipoScience, Diadexus and Reliant

Pharmaceuticals, LLC.

This article includes discussion of off-

label use of medications.

Submitted: May 29, 2007. Accepted: July

23, 2007.

References

1. Reaven GM. Role of insulin resistance in human dis-ease. Diabetes 1998;37:1595-1607.

2. American Heart Association. Women and cardiovas-

cular disease facts. Available at www.americanheart.org/presenter.jhtml?identifier=3039318. Accessed 5/27/07.

3. Polotsky AJ, Santoro N. Menopause and cardiovascu-lar disease: endogenous reproductive hormone exposureaffects risk factors. Menopause Management2007;16:21-25.

4. Grundy SM. Metabolic syndrome: connecting andreconciling cardiovascular and diabetes worlds. J Am CollCardiol2006;47:10931100.

5. Kahn R, Buse J, Ferrannini E, et al. The metabolicsyndrome: time for a critical appraisal: joint statementfrom the American Diabetes Association and the Euro-pean Association for the Study of Diabetes. DiabetesCare 2005;28:22892304.

6. Blaha M, Elasy TA. Clinical use of the metabolicsyndrome. Why the confusion? Clin Diabetes 2006;24:125-131.

7. Schneider JG, Tompkins C, Blumenthal RS. Themetabolic syndrome in women. Cardiology Rev2006;14:1-6.

8. Deedwania P, Barter P, Carmena R, et al; Treating toNew Targets Investigators. Reduction of low-densitylipoprotein cholesterol in patients with coronary heart dis-ease and metabolic syndrome: analysis of the Treating toNew Targets study. Lancet2006;368:919-28.

9. Grundy SM, Cleeman JI, Daniels SR, et al. AmericanHeart Association; National Heart, Lung, and Blood Insti-tute: Diagnosis and management of the metabolic syn-drome. Circulation 2005;112:273552.

10. Rutter M, Meigs J, Wilson P. Cardiovascular risk andthe metabolic syndrome. Metabolic Syndrome and Re-lated Disorders 2006;4:252-60.

11. Mosca L, Banka CL, Benjamin EJ, et al, for the ExpertPanel/Writing Group. Evidence-based guidelines for car-diovascular disease prevention in women: 2007 update.Circulation 2007;115:1481-1501.

12. Bax JJ, Inzucchi SE, Bonow RO, et al. Cardiac imag-ing for risk stratification in diabetes. Diabetes Care2007;30:1295-1304.

13. Lorenzo C, Williams K, Hunt K, Haffner SM. The Na-tional Cholesterol Education ProgramAdult TreatmentPanel III, International Diabetes Federation, and WorldHealth Organization definitions of the metabolic syndromeas predictors of incident cardiovascular disease and dia-betes. Diabetes Care 2007;30:8-13.

14. Schneider JG, Tompkins C, Blumenthal RS. Themetabolic syndrome in women. Cardiology Rev2006;

14:1-6.

PPharmacologic

(orlistat and

sirbutramine) and

bariatric surgery

approaches to weight

reduction seem

promising, although

clinical correlation

with event reduction

awaits further

research.


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15. Dekker JM, Girman C, Rhodes T, et al. Metabolicsyndrome and 10 year cardiovascular disease risk in the

Hoorn study. Circulation 2005;112:666-73.

16. Liu J, Grundy SM, Wang W, et al. Ten year risk of car-diovascular incidence related to diabetes, prediabetes andthe metabolic syndrome. Am Heart J2007;153:552-58.

17. Isomaa B, Almgren P, Tuomi T, et al. Cardiovascularmorbidity and mortality associated with the metabolic syn-drome. Diabetes Care 2001;24:683-89.

18. Jeppesen J, Hansen TW, Rasmussen S, et al. Insulinresistance, the metabolic syndrome, and risk of incident car-diovascular disease. J Am Coll Cardiol2007;49:2112-19.

19. Gami A, Witt BJ, Howard DE, et al. Metabolic syn-drome and risk of incident cardiovascular events anddeath: a systematic review and meta-analysis of longitudi-nal studies. J Am Coll Cardiol2007;49:403-14.

20. Tanko LB, Bagger YZ, Qin G, et al. Enlarged waist

combined with elevated triglycerides is a strong predictorof accelerated atherogenesis and related cardiovascularmortality in postmenopausal women. Circulation 2005;111:1883-90.

21. Sarwar N, Danesh J, Eriksdottir J, et al. Triglyceridesand the risk of coronary heart disease. 10,158 incidentcases among 262,525 participants in 29 westernprospective studies. Circulation 2007;115:450-58.

22. Bansal S, Buring J, Rifai N, et al. Fasting comparedwith nonfasting triglycerides and risk of cardiovascularevents in women. JAMA. 2007;298:309-16.

23. Sattar N, Gaw A, Scherbakova O, et al. Metabolicsyndrome with and without C-reactive protein as a predic-tor of coronary heart disease and diabetes in the West ofScotland Coronary Prevention study. Circulation 2003;108:414-19.

24. Wilson PW, DAgostino RB, Parise H, et al. Metabolicsyndrome as a precursor of cardiovascular disease andtype 2 diabetes mellitus. Circulation 2005; 112:306 6-72.

25. Kurl, S, Laukkanen JA, Niskanen L, et al. Metabolicsyndrome and the risk of stroke in middle-aged men.Stroke 2006 37:80611.

26. Ford ES, Giles WH, Dietz, WH. Prevalence of themetabolic syndrome among US adults. Findings from theThird National Health and Nutrition Examination Survey.JAMA 2002;287:356-59.

27. Bays H, Dujovne C. Adiposopathy is a more nationaltreatment target for metabolic disease than obesity alone.Curr Atheroscler Rep 2006;8:144-56.

28. Kip KE, Marroquin OC, Kelley DE, et al. Clinical im-portance of obesity versus the metabolic syndrome in car-diovascular risk in women. Circulation 2004;109:706-13.

29. Lamarche B, Tchernof A, Dagenais GR, et al. Small,dense LDL particles and the risk of ischemic heart dis-ease. Prospective results from the Quebec Cardiovascu-lar Study. Circulation 1997;95:6975.

30. Grundy SM, Cleeman JI, Bairey N, et al, for the Coor-dinating Committee of the National Cholesterol EducationProgram. Implications of Recent Clinical Trials for the Na-tional Cholesterol Education Program Adult TreatmentPanel III Guidelines. Circulation. 2004;110:227-39.

31. Barter PJ, Ballantyne CM, Carmena R, et al. Apo Bversus cholesterol in estimating cardiovascular risk and inguiding therapy: report of the thirty-person/ten countrypanel. J Intern Med2006;259:24758.

32. Mudd J, Borlaug B, Johnston P, et al. Beyond low-density lipoprotein cholesterol: defining the role of low-

density lipoprotein heterogeneity in coronary arterydisease. JACC 2007:50:1735-41.

33. Liu J, Sempos C, Donahue R, et al. Non-high-densitylipoprotein and very-low-density lipoprotein cholesterol

and their risk predictive values in coronary heart disease.Am J Cardiol2006;98:1363-68.

34. Cromwell W, Otvos J. Low-density lipoprotein particlenumber and risk for cardiovascular disease. Curr AtheroscleRep 2004, 6:38187.

35. Bays H, Abate N, Chandalia M. Adiposopathy: sickfat causes high blood sugar, high blood pressure and dys-lipidemia. Future Cardiol2005;1:3959.

36. Dayspring T. Cardiovascular disease: a comprehen-sive primer for clinicians. Menopause Management2002;11:1-9.

37. Cromwell W, Otvos J. Heterogeneity of low-densitylipoprotein particle number in patients with type 2 dia-betes mellitus and low-density lipoprotein cholesterol


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What is metabolic syndrome? Why is it a concern?

Metabolic syndrome is a disorder that affects the waythe body metabolizes fat and sugar. It can occur inthose who have too much waistline fat and who in-herit this tendency. With more Americans being over-

weight and obese, metabolic syndrome is becomingincreasingly common. The metabolic syndrome hasbeen thought of as a prediabetic syndrome, butdoctors increasingly regard it as a precoronarysyndrome (a condition that increases the risk ofheart disease). Metabolic syndrome greatly increases

your long-term risk of cardiovascular events, such asheart attacks, strokes and sudden death, and alsodramatically increases your risk of type 2 diabetes.

Who is at risk for metabolic syndrome?

Metabolic syndrome affects women more severelythan men, and it is more likely to occur at menopause

and beyond. Where a woman accumulates fat in herbody is an important factor in determining whethershes at higher risk for metabolic syndrome. Theapple shape is a higher-risk situation than the pearshape. Excessive waistline fat causes sick fat cells,

which produce a toxic stew of substances, increas-ing a womans risk of developing cardiovasculardisease and diabetes.

How is metabolic syndrome diagnosed?

Metabolic syndrome is diagnosed if you have 3 of the

following 5 conditions: Waist (at the top of the hip) measures more than35 inches (more than 31 inches in South Asians)

Blood pressure is over 130/85 mmHg (or youre al-ready taking blood-pressure-lowering medications)

High-density lipoprotein (good) cholesterol(HDL-C) is less than 50 mg/dL (or youre alreadytaking medication for low HDL-C)

Triglyceride (TG) level is over 150 mg/dL (oryoure taking medication for elevated TG)

Fasting blood sugar is greater than 100 mg/dL (or

youre taking medication to lower blood sugar)

As the number of these risk factors increases, sodoes your risk for cardiovascular disease.

Fortunately, metabolic syndrome is treatable andmost of the events associated with it are preventable.The key to reversing this process is a commitment tomodest weight loss and regular exercise. You need tomake a specific contract for goals with your health-care provider, and you need to implement self-

monitoring to follow your progress.


Resources

http://www.goredforwomen.org

http://www.womenheart.org/index.asp http://www.hearthealthywomen.org

http://www.menopause.org

http://www.thewalkingsite.com

More detailed lipid and lipoprotein information canbe found at:

http://www.lipoprofile.com/index.cfm

http://cks.library.nhs.uk/lipids_management/in_depth/background_information

Metabolic Syndromeand Menopause

Physiciansareencouragedtocopyanddistributethispatientinformationhandout.

Patient Information


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M M

Your Treatment Goals:

Weight reduction of 10% over 1 year (with the eventualgoal of attaining your ideal body weight).

YOUR WEIGHT-LOSS GOAL:is to weigh less than ________________ lbs.

(90% of your current body weight.)

DietFollow a reduced-calorie diet with carbohydrates that arelow on the glycemic index (GI) (visit www.glycemicindex.com). The glycemic index ranks carbohydrates accordingto their effect on blood sugar. Foods low in GI carbohy-drates create smaller changes in your levels of blood sugarand insulin, and are key to losing weight, maintainingweight loss, and lowering your risk of heart disease anddiabetes. (Visit http://www.americanheart.org/presenter.

jhtml?identifier=4644.]

Women should:

consume a diet rich in fruits and vegetables choose whole-grain, high-fiber foods limit alcohol intake to no more than 1 drink/day limit cholesterol to 300 mg/day limit intake of saturated (animal-derived) fats to 10% of

total calories (7% is even better) and keep consumptionof trans-fatty acids as low as possible

YOUR Diet Plan:

ExerciseExercise at least 30 min/day, with moderate to vigorousphysical activity on most days of the week. If walking andusing a pedometer, more than 10,000 steps/day is desir-able (adding over 1,000 kcal/week of exercise, ~20,000-25,000 steps/week) [1 mile walked = approximately 2000steps]. A physician should be consulted before begin-ning any rigorous exercise regimen.

YOUR Exercise Plan:

Lower your blood pressure if its high!A blood pressure reading of less than 120/80 mmHg is op-timal. Medications are recommended if your blood pressureis consistently higher than 130/80 mmHg.

YOUR blood pressure:_______________________________________

YOUR blood pressure medication: ______________________________________________

Keep your fasting blood sugar below 100 mg/dL (the optimal level).

YOUR fasting blood sugar: ___________________________________________________________________

YOUR blood-sugar reducing medication: ______________________

Goals for Cholesterol and Triglycerides: LDL (low-density lipoprotein, bad) cholesterol: LESS

THAN 100 mg/dL HDL (high-density lipoprotein, good) cholesterol:

GREATER THAN 50 mg/dL Triglycerides: LESS THAN 150 mg/dL Non HDL-cholesterol (total cholesterol minus HDL

cholesterol): LESS THAN 130 mg/dL

Traditional cholesterol and triglyceride measurements meas-ure fat (lipids) in the blood. In metabolic syndrome thesemeasurements less accurately predict the number of lipopro-tein particles implicated in causing cardiovascular diseases.Your doctor will use different goals, and perhaps advancedtests such as ApoB and NMR LDL-P to more accuratelycount the atherosclerosis-causing lipoprotein particles.

YOUR LIPID Value(s):

Future Risk of Heart DiseaseYour risk of having a heart attack within 10 years is esti-mated in a calculation called the Framingham Risk Score(FRS). The FRS is designed for adults age 20 years andolder who do not have heart disease or diabetes. To cal-culate your FRS, visit http://hp2010.nhlbihin.net/atpiii/calculator.asp.

YOUR Framingham Risk Score:

Women at moderately high risk (with a 10-20% 10-yearrisk) and high-risk patients ( >20% 10-year risk OR knowncoronary disease, diabetes or their equivalents) should havea non-HDL cholesterol goal of LESS THAN 130 mg/dL.Very high-risk women should have an even lower non-HDLcholesterol goal (LESS THAN 100 mg/dL).

Your doctor will discuss the need for cholesterol/lipoprotein-lowering medicines to help you reach these goals.

YOUR medications are:

Additional Advice:Stop smoking and avoid environmental smoke exposure.The following are recommended for most menopausalwomen with metabolic syndrome unless contraindi-cated by certain medical conditions. Talk to your doc-tor about whether you should NOT take: daily aspirin therapy to prevent heart attack Omega-3 fatty acid supplements that contain 850-1,000

mg/day of the active ingredients DHA and EPA.

Patient Information

Documents

Diagnosis and Treatment of Metabolic Syndrome in Menopausal Women