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Culture Documents
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Diagnosis and Treatment of Metabolic tends the concept of CVD risk and largely attributable to the accom-
Syndrome in Menopausal Women should not be viewed as a competi- panying metabolic abnormalities
(continued from page 16) tor to the FRS tool, but rather as of metabolic syndrome rather than
an enhancement.4 the hyperglycemia alone.16
morbidity or mortality from ASCVD Metabolic syndrome had an ad-
or from T2DM. (Post hoc analysis does Metabolic Syndrome in Women: verse impact on CVD health and
reveal that patients with metabolic What Studies Show mortality in the Botnia Study,17 a
syndrome derive incremental benefit Although no studies have specifi- prospective 7-year trial with more
from intensified statin therapy8). cally looked at menopausal women, than 3,000 patients (average age of
Regardless of whether metabolic multiple studies (the San Antonio women, >50 years). There was a 2-
syndrome is ultimately determined Heart Study, the Atherosclerosis to 3-fold relative risk increase in
to be a distinct biological entity, a Risk in Communities study, the total mortality, CHD mortality,
diagnosis serves to identify patients Hoorn study, and the Health, Aging CHD incidence, myocardial infarc-
at a two- to three-fold increased risk and Body Composition study) have tion and stroke (Figure 1).17
for ASCVD, who might benefit suggested that the metabolic syn- The recently completed Monitor-
from more intensive lifestyle and, drome may be more predictive of ing of Trends and Determinants in
possibly, pharmacologic therapy.9 CHD events in women than in Cardiovascular Disease trial18 is a
The predictive value of metabolic men.13-15 A recent, 10-year, prospec- prospective Danish population-
syndrome has generally not been tive multicenter trial in China of ap- based study of 2,493 men and
shown it to be superior to the Fram- proximately 30,000 subjects showed women, ages 41 to 72 years, without
ingham Risk Score (FRS) in delin- that metabolic syndrome signifi- major CVD at baseline. Over a me-
eating short-term (10-year) ASCVD cantly increased CVD risk com- dian follow-up of 9.4 years, the rel-
risk.10 However, the diagnosis of pared with patients who do not ative risk (RR) of cardiovascular end
metabolic syndrome remains a have metabolic syndrome but who points (CV death, nonfatal ischemic
strong predictor of long-term coro- do have hyperglycemia. The risk heart disease and nonfatal stroke,
nary heart disease (CHD) risk and of CVD in this population was adjusted for age, gender, smoking
identifies potentially high-risk pa-
tients, especially in women over 55
years of age. A diagnosis of meta-
bolic syndrome identifies those at
risk for T2DM and stroke; the FRS
does not. The FRS may, in fact, se-
riously underestimate lifetime car-
diovascular risk in women.11
Thus, clinicians face a dilemma
with regard to accurate risk predic-
tion and treatment, and may need to
resort to additional tools, such as
imaging studies, biomarkers and ad-
vanced lipoprotein analysis to aug-
ment the FRS. However, validation
of cardiac imaging and biomarkers
as tools to screen for long-term risk Figure 1. Metabolic syndrome has a negative impact on CV health
in insulin-resistant states awaits and mortality.17
prospective trial data.12 The diag-
nosis of metabolic syndrome ex-
and low-density lipoprotein choles- elevated triglycerides and elevated be adapted for multiethnic popula-
terol [LDL-C]) was increased by waist added little to risk prediction in tions; for example, by reducing the
1.56 (95% confidence interval [CI], this model. The authors concluded criterion for elevated waist circum-
1.12 to 2.17).18 The authors con- that the presence of EWET may be ference in South Asian women. The
cluded that both insulin resistance the best indicator of cardiovascular incidence of the metabolic syndrome
and metabolic syndrome, as defined risk in menopausal women. New increases with age; the prevalence of
by the National Cholesterol Educa- studies confirm that both fasting metabolic syndrome increased from
tion Program Adult Treatment Panel and nonfasting triglycerides are im- approximately 7% among partici-
(NCEP-ATP III), independently portant independent risk factors for pants between ages 20 and 29 to ap-
predict cardiovascular disease. cardiovascular events.21,22 proximately 43% for patients over
A new meta-analysis of 40 studies 60 years of age.26 The prevalence of
varying in length from 2 to 16 years The Role of Risk Factors metabolic syndrome differs with
in 172,573 individuals, using end- The incidence of new-onset T2DM, race, with the age-adjusted preva-
points of new heart disease events or a CHD relative risk equivalent in lence being highest among Mexican-
death, showed metabolic syndrome the NCEP guidelines, correlates American individuals and lowest
had an RR of 1.78 (95% CI, 1.58- with the number of characteristics, among African-Americans and peo-
2.00). The association was stronger or risk factors, of metabolic syn- ple of other racial categories. The
in women than in men (RR, 2.63 vs. drome. Patients with four or five risk most recent data suggest that ap-
1.98, P = 0.09.) Multivariate analy- factors for metabolic syndrome have proximately 50 million Americans
sis adjusting for the individual com- a 24-fold greater risk for T2DM have metabolic syndrome.
ponents of metabolic syndrome compared with patients who have
demonstrated cardiovascular risk no risk factors.23 There is also evi- Pathophysiology
beyond that associated with its in- dence that CHD risk increases with The pathophysiology of metabolic
dividual risk factors (RR, 1.54; 95% the number of components of meta- syndrome involves dysfunctional
CI, 1.32-1.79).19 bolic syndrome,24 as does ischemic adipocytes (adiposopathy). Adipo-
The Enlarged Waist/Elevated stroke risk (two to three times in- sopathy is defined as pathologic
Triglycerides (EWET) trial was the creased relative risk).25 Analysis of adipose tissue dysfunction that may
first long-term prospective study of the Framingham Offspring Study be initiated and/or exacerbated by
metabolic syndrome risk factors in (1,774 women, average age >50 years) fat accumulation in genetically sus-
a community-based, menopausal- revealed significant increases in total ceptible patients.27 Increased vis-
specific population.20 Rather than CVD and hard CVD outcomes (my- ceral adipose tissue dysfunction
investigating all the factors of ocardial infarction or CHD death) often correlates with the amount of
metabolic syndrome as defined by with the diagnosis of metabolic visceral adipose tissue and also with
the American Heart Association/ syndrome.24 The increases in these an increased number of metabolic
National Heart, Lung, and Blood events were steeper in women than in syndrome components (“score”).
Institute (AHA/NHLBI), EWET men, which correlated with the num- The Women’s Ischemia Syndrome
used only the two parameters of en- ber of metabolic syndrome risk fac- Evaluation (WISE) study demon-
larged waist size (over 35 inches) tors present (Table 1). Increases in strated the importance of where a
and elevated triglycerides (≥128 relative risk of T2DM were greater menopausal woman’s body fat is
mg/dL) in estimating cardiovascular than increases in CVD events. mainly located.28 The odds ratio of
mortality in 557 menopausal women significant coronary artery disease
ages 48 to 76, who were followed Diagnostic Criteria by angiography was related to the
prospectively for 8.5 years. Mortality The AHA/NHLBI diagnostic crite- presence or absence of metabolic
was increased almost 5-fold by the ria for metabolic syndrome (Table 2) syndrome at any weight, even in the
presence of EWET, and metabolic are well known and are discussed in absence of obesity. The relative risk of
syndrome risk factors other than detail elsewhere.9 These criteria can mortality and CVD events was more
18 MENOPAUSE MANAGEMENT
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traditional” risk factors that confers 1. Waist >35 inches in women ( >31 inches in South Asians)
a dramatic increase in CVD risk: 2. Triglycerides >150 mg/dL (or on drug treatment with a fibrate or niacin for elevated TG)
• hyperinsulinemia, 3. HDL-C < 50 mg/dL (or on drug treatment with a fibrate or niacin for low HDL-C)
• small, dense LDL particles, and 4. SBP ≥130 or DBP ≥85 mm Hg (or on antihypertensive drug treatment)
• an elevated number of athero- 5. Fasting plasma glucose >100 mg/dL (or on drug treatment for elevated glucose)
genic ApoB lipoprotein particles.
TG = triglycerides; DBP = diastolic blood pressure; HDL-C = high-density lipoprotein cholesterol;
SBP = systolic blood pressure
The risk of ischemic heart dis-
ease is differentially increased ac-
cording to the cumulative number the presence of major risk factors emphasis from a lipid-concentra-
of traditional and nontraditional (family history of premature CVD, tion risk management strategy to
risk factors. The presence of the low high-density lipoprotein cho- a lipoprotein-concentration risk
atherogenic triad confers an almost lesterol [HDL-C], age, smoking management strategy.31,32 Although
21-fold increased relative risk over history and hypertension) and the we have traditionally used plasma
patients in a similar quartile of tra- FRS. Intensity of treatment of plasma lipid (cholesterol and triglyceride)
ditional risk factors.29 lipid concentrations is directly pro- concentrations as determined by
The NCEP-ATP III 2004 ad- portional to the risk predicted by the standard lipid panel (total-
dendum guidelines recommend this algorithm.30 However, there are cholesterol, LDL-C, HDL-C, very
classification of risk according to distinct advantages in shifting the low-density lipoprotein cholesterol
[VLDL-C] and triglycerides), it is excessive concentration of NEFAs cholesterol (TC)/HDL-C and tri-
now well established from epidemi- (and/or when augmented by an ex- glycerides (TG)/HDL-C ( >4:1 is
ologic and clinical trials that, in cessive simple carbohydrate diet), abnormal) ratios.36 The scenario of
fact, CVD risk tracks more closely triglyceride synthesis is initiated. normal LDL-C associated with el-
with plasma lipoprotein concentra- The liver is not adapted to handle evated non-HDL-C, or abnormal
tions.31,32 This is especially true in an excessive load of triglycerides. TC/HDL-C or TG/HDL-C ratios
insulin-resistant populations. Hypertriglyceridemic situations like can be used to identify elevated
Plasma lipoprotein concentra- metabolic syndrome lead to an over- ApoB and likely contributes to the
tions are better than any of the production of large triglyceride-rich residual CV risk so common in
plasma cholesterol indices at assess- ApoB-containing VLDLs, which these patients.34,37
ing residual risk patients’ experience are associated with fasting and Low HDL-C is the most com-
after they’ve begun treatment. postprandial hypertriglyceridemia. mon abnormality associated with
Apolipoprotein B is a surface pro- Triglyceride-rich VLDLs, them- CVD events in the Framingham
tein component of atherogenic selves highly atherogenic, are subject study and is often associated with
lipoproteins (LDL, VLDL, inter- to altered lipolysis, which creates insulin-resistant syndromes like
mediate density lipoproteins and smaller VLDL particles (remnants) metabolic syndrome. Low HDL-C
remnant particles). Each of these and small, dense LDL and HDL is often associated with increased
lipoproteins contains a single mole- particles. This process results in low numbers of atherogenic VLDL
cule of ApoB. Cardiovascular risk is HDL-C and HDL particle counts remnants and small LDL particles.
increased by an increased ApoB par- (HDL-P). Patients with small LDL Also contributing to the risk is the
ticle concentration. ApoB determi- particles typically have high LDL-P altered functionality of HDL parti-
nation is simple, standardized and (ApoB) concentrations.31 Since many cles common in proinflammatory
directly measured (unlike LDL-C, metabolic syndrome patients with states like metabolic syndrome and
which is a calculated value). An eas- small LDL particles have low T2DM. Inflammatory proteins ren-
ily calculated non-HDL-C value HDL-C, they will often have ab- der HDL particles less efficacious
(total-cholesterol concentration mi- normalities of non-HDL-C, total at performing macrophage reverse
nus the HDL-cholesterol concen-
tration) serves as an alternative
validated tool for assessment of risk
from all circulating ApoB parti-
cles.33 LDL particle concentration
(LDL-P) determined by nuclear
magnetic resonance imaging is an
alternative method for determining
plasma lipoprotein concentration-
associated risk.34
The lipoprotein abnormalities of
metabolic syndrome are an exces-
sive number of atherogenic ApoB
lipoprotein particles, accompanied
by reduced numbers, as well as dys-
function, of HDL particles (Figure
2). Under conditions of adiposopa-
thy, visceral fat cells are unable to
Figure 2. Lipoprotein abnormalities of insulin resistance/adiposopathy.
properly control and store NEFAs.35
When the liver is confronted with an
20 MENOPAUSE MANAGEMENT
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cholesterol transport, and delivering pose tissue dysfunction, not neces- physical activity on most days of
anti-inflammatory, anticoagulant sarily reduction in adipose tissue the week. If this activity is weight-
and profibrinolytic proteins to areas mass. The establishment of a meta- bearing, the dual benefit of potential
of arterial plaque. It is becoming ev- bolic syndrome clinic in the health- prevention of menopausal osteo-
ident that the new term “HDL care provider’s office to specifically porosis can also be accomplished.
functionality” is likely very impor- target and treat metabolic syndrome The use of inexpensive pedometers
tant in atherogenesis. Therapeuti- through therapeutic lifestyle change to set and track goals for the simplest
cally improving HDL functionality is a promising approach, as intensive form of modest-intensity exercise—
may be more important than in- lifestyle modification has been walking—is practical and effective;
creasing HDL-C.38,39 shown to improve components of more than 10,000 steps/day is con-
metabolic syndrome.40-42 Thera- sidered an “active” lifestyle. An ex-
Treatment peutic lifestyle change in metabolic ercise prescription of adding >1,000
The 2007 AHA guidelines for the syndrome consists of promotion of kcal/week of exercise (~20,000-
prevention of cardiovascular disease daily moderate-intensity exercise, 25,000 steps/week) consisting of
risk in women emphasize the as- modest weight reduction, a healthy moderate-intensity walking is rec-
sessment of lifetime risk in women low glycemic index or Mediter- ommended.43 Patients should be re-
instead of the previous emphasis ranean-style diet and increased con- minded that regardless of any weight
upon assessment of short-term risk.10 sumption of omega-3 fatty acids loss achieved, physical activity is in-
The Framingham risk paradigm is (Table 3). Modest weight reduction sulin sensitizing and is of cardiores-
excellent at assessing 10-year risk in (5-10%) and walking 150-180 piratory and psychological value.44
women, but we now have substantial min/week improves many of the Goals for an individualized diet
data showing that even the presence physiologic abnormalities of meta- include a reasonable reduction in
of one major cardiovascular risk fac- bolic syndrome and slows the pro- weight of 7% to 10% over 1 year,
tor in a woman over 50 years of age gression to T2DM. Self-monitoring with the eventual goal of obtaining
will increase her lifetime risk for of parameters such as food intake, ideal body weight. This is achieved
cardiovascular disease dramatically. body weight and exercise level is by the initiation of reduced caloric
There is also evidence that there is critical for success. Exercise man- intake and reduced consumption of
a broad heterogeneity of risk pres- agement should consist of at least 30 simple carbohydrates, under the su-
ent in women with a given FRS. A minutes of moderate-to-vigorous pervision of a clinical nutritionist if
high-risk FRS (>20%) identifies
women at high risk, but a lower score
is not sufficient to ensure that an indi- Table 3. Implementing Therapeutic Lifestyle Changes
vidual woman is at low risk. The com- • Specific contract with patient for goals and self-monitoring.
bined use of metabolic syndrome
• Exercise — at least 30 minutes of moderate to vigorous physical activity on most
diagnosis with a lipoprotein particle-
days of the week. Using pedometer, walking >10,000 steps/day is desirable.
based treatment approach provides a
rational approach to management of • Diet – reduction of weight by 7-10% over 1 year with reduced caloric intake and
reduced consumption of simple carbohydrates (low glycemic index diet). Women
risk in menopausal women. should consume a diet rich in fruits and vegetables; whole-grain, high-fiber foods;
Therapeutic lifestyle change. The limited intake of saturated fat to 10% of energy (if possible to 7%); cholesterol to
goals of treatment in metabolic syn- 300 mg/d; no more than 1 alcoholic drink per day; consumption of trans-fatty acids
drome are to simultaneously de- (FA) should be as low as possible.
crease the instance of CHD events • Increased omega-3 FA consumption (~850-1000 mg EPA + DHA / day)
and to prevent or delay the devel-
• Women should not smoke and should avoid environmental tobacco smoke.
opment of T2DM. The cornerstone
EPA=eicosapentaenoic acid; DHA=docosahexaenoic acid
of treatment is therapeutic lifestyle
change directed at improving adi-
22 MENOPAUSE MANAGEMENT
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possible. Attainment of ideal body number of circulating triglyceride- multiple genes involved with glucose
weight is obviously difficult in this rich VLDL particles driving the and fatty acid metabolism, lipopro-
population, but even modest weight lipoprotein abnormalities of meta- tein synthesis and catabolism, and
loss has been associated with labo- bolic syndrome, by either reducing vascular inflammation. They de-
ratory improvement and clinical risk their production in the liver or in- crease the hepatic production of
reduction.40 Increased soluble fiber creasing their catabolism, with fi- triglycerides, increase the catabolism
intake and reduction of saturated brates, niacin or high-dose omega-3 of triglyceride-rich lipoproteins and
and trans fatty acid intake are to be fatty acids. The fibrates regulate increase the synthesis and function-
recommended as well. Plant stanol
esters significantly lower LDL-C
and are available in various “func- Table 4. Metabolic Syndrome – Pharmacologic Treatment 9,11,31,32
tional foods.”45 Increased omega-3
• Assessment and treatment of risk using an atherogenic particle-based
fatty acid consumption (approxi-
approach (instead of a traditional lipid-based approach)
mately 1,000 mg of eicosapentaenoic
acid [EPA] and docosahexaenoic • Primary goal: reduce atherogenic ApoB particles to physiologic levels
acid [DHA] per day) reduces risk in • Lifestyle approaches should be encouraged to reach the following optimal lipid levels:
women with CVD, and it is reason- ➣ LDL-C < 100 mg/dL
able to extend this treatment to ➣ HDL-C > 50 mg/dL
high-risk patients such as those with ➣ TG < 150 mg/dL
metabolic syndrome. ➣ Non HDL-C < 130 mg/dL
Pharmacologic treatment. Pharma-
cologic treatment of cardiovascular • Framingham Risk Scoring should be done to stratify absolute 10-year risk of ASCVD.
risk in metabolic syndrome is based • Goals of treatment for those at moderately high risk (≥ 2 risk major risk factors, with
on the assessment and treatment of 10-20% risk) and high-risk patients (known CVD or T2DM or CHD equivalent*):
risk using an atherogenic particle- Non-HDL-C < 130 mg/dL OR ApoB < 80 mg/dL OR NMR LDL-P < 1000 nMol/L
based approach.46 Aggressive treat- • Very high-risk women (established CVD plus any of the following: MetSyn, multiple
ment is safe, effective and well major risk factors, severe and poorly controlled risk factors, T2DM) have lower goals:
within the scope of practice of all Non-HDL-C < 100 mg/dL OR ApoB < 60 mg/dL OR NMR LDL-P < 1000 nMol/L
primary care providers,47 and need
• Statin is first-line Rx to reduce ApoB particles.
not be left to internists and cardiol-
ogists once risk is identified. • If not at non-HDL-C, ApoB or LDL-P goal, add fenofibrate. Ezetimibe or bile acid
An aggressive goal is to reduce sequestrant or Rx extended-release niacin can be added if goal not attained.
the atherogenic ApoB particle count • Aggressive hypertension control. Optimal BP < 120/80. Treat to < 130/80, with
to physiologic levels associated with ACE inhibitors/ARBs preferred, with thiazide diuretics next if needed.
low CVD risk (Table 4). Statin • Management of hyperglycemia (FBS > 100 mg/dL ) with metformin, especially
drugs inhibit cholesterol synthesis in with an abnormal glucose tolerance test.
almost all cells, although the liver is
• 81- to 162-mg enteric-coated aspirin, unless contraindicated.
the organ that clears ApoB parti-
cles. The largest body of evidence • Weight-loss medications or bariatric surgery may be helpful in some patients.
for pharmacologic risk reduction in *“CHD equivalent” = known peripheral arterial disease, abdominal aortic aneurysm, carotid
insulin-resistant patients exists for artery disease, chronic renal disease (creatinine > 1.2 mg/dL)
statins. First-line pharmacologic
LDL-C = low-density lipoprotein cholesterol; HDL-C= high-density lipoprotein cholesterol;
strategy to reduce ApoB-containing TG = triglycerides; ASCVD = atherosclerotic cardiovascular disease; T2DM = type 2 diabetes mellitus;
particles would be appropriately CHD = coronary heart disease; Apo-B = apolipoprotein B; NMR = nuclear magnetic resonance;
MetSyn = metabolic syndrome; LDL-P = LDL particle concentration; FBS = fasting blood sugar
dosed statin therapy. A complemen-
tary strategy would be to reduce the
24 MENOPAUSE MANAGEMENT
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All patients with a >10% 10-year 2. American Heart Association. Women and cardiovas-
cular disease facts. Available at www.americanheart.org/
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Gregory S. Pokrywka, MD, FACP, is Assis-
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tant Professor of Medicine at Johns Hop-
patients may have only modest kins University School of Medicine,
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26 MENOPAUSE MANAGEMENT
Patient Information
Metabolic Syndrome
and Menopause
What is metabolic syndrome? Why is it a concern? and beyond. Where a woman accumulates fat in her
Metabolic syndrome is a disorder that affects the way body is an important factor in determining whether
the body metabolizes fat and sugar. It can occur in she’s at higher risk for metabolic syndrome. The
those who have too much waistline fat and who in- “apple shape” is a higher-risk situation than the “pear
herit this tendency. With more Americans being over- shape.” Excessive waistline fat causes “sick fat cells,”
weight and obese, metabolic syndrome is becoming which produce a “toxic stew” of substances, increas-
increasingly common. The metabolic syndrome has ing a woman’s risk of developing cardiovascular
been thought of as a “prediabetic” syndrome, but disease and diabetes.
doctors increasingly regard it as a “precoronary”
syndrome (a condition that increases the risk of How is metabolic syndrome diagnosed?
heart disease). Metabolic syndrome greatly increases Metabolic syndrome is diagnosed if you have 3 of the
your long-term risk of cardiovascular events, such as following 5 conditions:
heart attacks, strokes and sudden death, and also • Waist (at the top of the hip) measures more than
dramatically increases your risk of type 2 diabetes. 35 inches (more than 31 inches in South Asians)
Physicians are encouraged to copy and distribute this patient information handout.
28 MENOPAUSE MANAGEMENT