1
Florida Heart CPR*
Diet, Weight Loss and Cardiovascular Disease
3 hours
Learning Objectives
Upon completion of this activity, participants should be able to:
1. Define the role of obesity in the development of cardiovascular risk factors
2. Explain the links between the metabolic syndrome, cardiovascular disease
(CVD), and obesity
3. Discuss the importance of lifestyle modification in the reduction of CVD risk
4. Detail the benefits and drawbacks of dietary, behavioral, and pharmacologic
interventions for weight loss
Assessing Cardiovascular Disease Risk
When patients are seen in everyday medical practice, how does a clinician determine
their risk for cardiovascular disease (CVD)? First, each patient should be thoroughly
evaluated and clinicians should take a medical inventory of both traditional and
"nontraditional" CVD risk modifiers (Table 1).[1-4]
Table 1. Traditional and Nontraditional CVD Risk Factors
Traditional CVD Risk Factors
 Hypertension (blood pressure > 140/90 mm Hg or on antihypertensive
medication)

Dyslipidemia: high levels of low-density lipoprotein (LDL) cholesterol and low
levels of high-density lipoprotein (HDL) cholesterol

Diabetes

Cigarette smoking

Age: men > 45 years; women > 55 years

Overweight or obesity

Clinically apparent CVD including left ventricular hypertrophy, angina/prior
myocardial infarction (MI), prior coronary revascularization, and heart failure
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
Family history of CVD
Nontraditional CVD Risk Factors
 Elevated fasting insulin (impaired glucose tolerance)

Elevated low apolipoprotein B

Small dense LDL

Microalbuminuria

C-reactive protein
Of course, no risk factor should be considered in isolation. The most recent publications
from the National Heart, Lung, and Blood Institute (NHLBI) on managing high blood
pressure and dyslipidemia emphasize the importance of considering multiple (> 2) risk
factors in determining CVD risk.[1,2] Indeed, the recently released Third Report of the
National Cholesterol Education Program Expert Panel on Detection, Evaluation, and
Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III [ATP III]) uses
projections from the Framingham Heart Study of 10-year absolute coronary heart
disease (CHD) risk (ie, the percent probability of having a CHD event in 10 years) to
identify which patients with multiple risk factors require more intervention to prevent
cardiovascular disease. Furthermore, for the first time, the ATP III has called specific
attention to the importance of targeting the metabolic syndrome, a constellation of
cardiovascular risk factors including abdominal obesity, hypertension,
hypertriglyceridemia, and low levels of high-density lipoprotein (HDL) cholesterol, as a
new method of risk-reduction therapy.[2]
While each factor independently modifies the risk of CVD, they may not work just in
additive fashion, but also synergistically to multiply a person's risk.[5] Thus, clinicians
should determine a patient's CVD risk based on all potential risk modifiers. After all,
CVD is a progression that begins and continues through a complex interaction between
the environment and genetics.
In time, more and more CVD risk factors are sure to emerge, thereby providing further
targets for therapeutic intervention. Nevertheless, each and every risk factor should be
viewed in relation to the others when deciding upon intervention. In summary, clinicians
should view cardiovascular risk in a global way.
From Hypertension to CVD
Hypertension has a dramatic impact on CVD risk for people of all ages and both
sexes.[5-7] A 36-year follow-up of individuals aged 35-64 years in the Framingham Heart
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Study showed that hypertensive patients have an excess risk of CHD, stroke, peripheral
artery disease, and heart failure compared with patients with normal blood pressure.
Although numerous trials have shown that lowering blood pressure provides much
benefit, CVD is not eliminated. One reason for this lack of elimination is that
hypertension tends to cluster in patients with other cardiovascular risk factors, such as
abnormalities of glucose, insulin, and lipoprotein metabolism.[8] Furthermore,
hypertensive patients are more likely to be obese, to smoke cigarettes, and to have a
family history of CVD compared with their normal counterparts.[5-7] Adding any one of
these factors to a person's risk repertoire can double the CVD risk associated with
hypertension.[3] In addition, taken separately, each factor is a population marker for
CVD. Since these risk factors interact to promote heart disease, clinicians must
consider each individual's collective risk when treating hypertension.[9]
Interrupting the Cascade of CVD
Before any clinically apparent disease, patients often show other evidence of diffuse
vascular and organ damage, which ultimately progresses to morbid events. Ordinarily,
the changes that occur early in the cardiovascular continuum are subtle and difficult to
tease out. Discovering vascular endothelium dysfunction, changes in arterial
compliance or elasticity, arterial wall thickness, and left ventricular hypertrophy all
require imaging techniques. Microalbuminuria and vascular calcification are other
important, usually clinically silent, CVD markers.
Thus, the onus is on clinicians to probe for these markers of CVD. Identifying,
modifying, and treating these risk factors may halt the development and progression of
CVD.
The Fattening of America and CVD Risk
An estimated 61% of American adults are overweight, while 26% are obese, according
to results of the 1999 National Health and Nutrition Examination Survey (NHANES). [10]
Statistics reveal an increase in prevalence of obesity and overweight for both sexes, all
races/ethnicities, age groups, and educational levels in the United States since the
NHANES III survey was completed in 1994, and all measures suggest continuing trends
toward an ever-fatter America. From a global perspective, the increase in the
prevalence of obesity is similarly alarming.[11] Indeed, both the NHLBI and the World
Health Organization (WHO) have classified obesity as an epidemic. (The NHLBI defines
overweight as a body mass index [BMI, in kg/m2] of 25.0-29.9 and obesity as a BMI of
>/= 30.[12])
Overweight and obesity kill approximately 300,000 Americans annually, [13] taking an
economic toll of $117 billion each year.[14] Overweight and obesity have been shown to
sharply increase the risk of hypertension; stroke; endometrial, breast, prostate, and
colon cancers; gallbladder disease; osteoarthritis; sleep apnea; respiratory problems;
and CVD mortality.
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Diet, Weight Loss and CVD
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The burgeoning obesity epidemic has contributed to a concurrent explosion in the
prevalence of the metabolic syndrome and type 2 diabetes.[15-18] An estimated 16 million
Americans have diabetes, with type 2 diabetes accounting for up to 95% of these
cases.[19] This number is expected to grow as the population at large is aging and
becoming more obese and sedentary.[20,21] A host of studies have clearly established
that overweight and obesity are among the most important risk factors for developing
glucose intolerance and type 2 diabetes.[15-23] Of interest, CVD accounts for 75% of
diabetic mortality.[24]
Metabolic Syndrome: A Less Recognized Obesity-Associated Epidemic
Although a fasting glucose > 126 mg/dL is known to be associated with an elevated risk
of CVD, there is a continuum of CVD risk from normal glucose tolerance all the way
through to diabetes. It is somewhere in this range of CVD risk that the estimated 47
million Americans with the metabolic syndrome fall.[18]
The metabolic syndrome, also known as impaired glucose tolerance (IGT) or the insulinresistant syndrome, has been defined in a variety of ways but is predominantly
diagnosed by an insulin-resistant hyperinsulinemia in overweight individuals or in those
with abdominal obesity. At its essence, the metabolic syndrome is a cluster of
characteristics that together increase the risk of diabetes and CHD in addition to
numerous other health problems.
According to the ATP III,[2] individuals with 3 or more of the following characteristics
have the metabolic syndrome:





Abdominal obesity: waist circumference > 102 cm in men and > 88 cm in women
Hypertriglyceridemia: >/= 150 mg/dL (1.69 mmol/L)
Low high-density lipoprotein (HDL) cholesterol: < 40 mg/dL (1.04 mmol/L) in men
and < 50 mg/dL (1.29 mmol/L) in women
High blood pressure: >/= 130/85 mm Hg
High fasting glucose: 110 mg/dL (>/= 6.1 mmol/L)
Using data from NHANES III, Ford and colleagues[18] at the Centers for Disease Control
and Prevention (CDC) estimated an age-adjusted prevalence of the metabolic
syndrome of 23.7% in the United States. Thus, extrapolating out from 2000 census
data, about 47 million US residents have the metabolic syndrome. Furthermore, since
the prevalence of the metabolic syndrome increases with age, it is estimated to affect
more than 40% of Americans over 60 years of age.
Evaluating these data by ethnicity, Mexican Americans were at the highest risk for the
metabolic syndrome, with an age-adjusted prevalence of almost 32%.[18] Overall, the
age-adjusted prevalence was similar for men and women. African American women,
however, had an approximate 57% higher prevalence than their male counterparts.
Mexican American women also had a disproportionate risk, about 26% higher than
Mexican American men.
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According to the WHO, at least 200 million people worldwide have IGT.[25] Over the
course of 5 to 10 years, approximately 40% of these individuals will progress to
diabetes; the remainder will revert to normal glucose tolerance or will persist with IGT.
Obesity is Central to Mechanisms of the Metabolic Syndrome
Insulin resistance, often the first clinical marker of the metabolic syndrome, involves an
overproduction of glucose by the liver, impaired peripheral glucose utilization, and an
increased breakdown of fat, or lipolysis, leading to elevated levels of free fatty acids.
Abnormal fatty-acid metabolism and visceral adiposity are known to play important roles
in the metabolic syndrome.[25-27] Visceral adipose tissue is defined as adipose tissue
located in the deep region of the abdomen. Deep visceral adipose tissue is relatively
insensitive to the action of insulin and therefore undergoes lipolysis, breaking down
triglycerides to form free fatty acids.
In the liver, these free fatty acids drive glucose production. In addition, free fatty acids
are used in the liver to form triglycerides, thereby driving the production of very lowdensity lipoproteins (VLDLs). In addition, free fatty acids cause insulin resistance in
pancreas and skeletal muscle.[26] Free fatty acid elevation thus mediates resistance to
insulin at all 3 tissue sites. Indeed, studies show that obese individuals with high levels
of visceral adipose tissue have a much greater insulin response to oral glucose
tolerance tests compared with obese people who have little visceral adipose tissue.[28,29]
Insulin resistance and compensatory hyperinsulinemia are established features of
obesity. In Pima Indians, insulin sensitivity has been shown to decline with increasing
BMI.[30,31] While both genes and environment influence the development of insulin
resistance, obesity and a sedentary lifestyle have been shown to be the primary causes
of insulin resistance, IGT, and type 2 diabetes.[32,33]
In general, normoglycemia progresses to IGT, primarily due to increasing insulin
resistance.[34] Individuals adapt to increasing insulin resistance with increased beta-cell
mass and increased insulin secretion.[35] Both obese and insulin-resistant individuals
have been shown to have compensatory hyperinsulinemia in the fasting and
postprandial state.[36] Progression to diabetes occurs when beta cells cannot secrete
enough insulin to compensate for the insulin resistance.[35-40] As a result, postprandial
and fasting glucose levels increase, leading to IGT and/or the metabolic syndrome, and
eventually to full-blown diabetes.
Gradations of Cardiovascular Risk in Insulin Resistance
The dyslipidemia, hypertension, glucose intolerance, and hypercoagulability caused by
insulin resistance predispose an individual not only to diabetes, but also to coronary
artery disease, MI, and stroke. Haffner and colleagues[41] conducted a retrospective
analysis of the data from the Scandinavian Simvastatin Survival Study (4S), the first
secondary prevention study showing that 3-hydroxy-3-methylglutaryl coenzyme A (HMG
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CoA) reductase inhibitors (commonly known as statins) substantially reduce all-cause
mortality as well as cardiovascular events and mortality. Data analysis revealed a clear
gradation in risk of major CHD events depending upon levels of fasting glucose. The
portion of major CHD events increased from 25% among individuals with normal fasting
glucose to almost 50% for people with a known history of diabetes.
Despres and colleagues[42] examined the relationship between fasting insulin levels and
the risk of ischemic heart disease in men aged 45 to 76 who did not have diabetes. The
fasting plasma insulin concentrations in 91 patients who had experienced an ischemic
event were compared with concentration in 105 controls. At baseline, fasting plasma
insulin concentrations were 18% higher in the case patients than in the controls (P <
.001). In addition, fasting insulin concentration was directly associated with the risk of
ischemic heart disease.
The Honolulu Heart Study similarly demonstrated a direct relationship between
increasing postchallenge glucose concentration and CHD.[43] More than 6000
nondiabetic men aged 45-70 years were followed for 12 years. The rate of fatal CHD
and total CHD (defined as total CHD and nonfatal MI) increased directly with
postchallenge glucose concentration. Men in the fourth quintile of postchallenge glucose
(157-189 mg/dL) had twice the age-adjusted risk of fatal CHD compared with those in
the lowest quintile (40-115 mg/dL).
Reducing CVD Events in the Metabolic Syndrome
The well-established link between obesity, the metabolic syndrome, and CVD make
intervention in this population crucial to improving public health. Treatment of 3 main
disorders has been proven to reduce cardiovascular events in this high-risk group:
hypertension, dyslipidemia, and hypercoagulability. In addition, because obesity,
particularly central obesity, is at the fulcrum of the metabolic syndrome, any successful
approach in this population must effectively deal with the issue of obesity. As a result,
all pharmacologic interventions should be complemented with lifestyle approaches to
promote weight loss.
Hypertension
Hypertension is defined as systolic blood pressure (SBP) of > /= 140 mm Hg, diastolic
blood pressure (DBP) of >/= 90 mm Hg, or the use of antihypertensive drugs. [1] The
relationship between SBP and DBP and cardiovascular risk is well established:
Increases in DBP and SBP have been shown to be directly and continuously associated
with increases in CVD risk.[44,45]
Hypertensive individuals with 1 or more major CVD risk factors make up the bulk of the
hypertensive population.[46] Specifically, hypertension is prevalent among people with
the metabolic syndrome. Exercise and weight loss measures are no longer
recommended for 6 to 9 months before treating with antihypertensive medications in
these high-risk patients. Rather, guidelines now advise clinicians to consider
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Diet, Weight Loss and CVD
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hypertensive drugs as primary therapy.[1] Indeed, while concomitant lifestyle
modifications should be strongly recommended, their implementation should not delay
the initiation of pharmacologic therapy.
A number of large studies in diabetic persons with hypertension show important benefits
in CVD outcomes from lowering blood pressure.[47-49] In the UK Prospective Diabetes
Study Group, tight blood pressure control resulted in considerable clinical benefits for
diabetic patients.[47] Patients assigned to the tight blood control group (mean, 144/82
mm Hg) had a 24% reduction in any diabetes-related end point, a 56% reduction in
heart failure, and a 32% reduction in diabetes-related deaths compared with patients
assigned to less the aggressive blood pressure control group (mean, 154/87 mm Hg)
The percent risk reduction was similar in patients treated with an angiotensin-converting
enzyme (ACE) inhibitor or a beta-blocker.[47]
The Hypertension Optimal Treatment (HOT) trial[48] examined the effects of blood
pressure lowering on more than 18,000 hypertensive patients, 1501 with diabetes.
Study results showed that aggressive DBP lowering to levels < 85 and 80 mm Hg was
associated with a 51% reduction in the risk of major cardiovascular events (P = .005)
and a 43% reduction in the risk of cardiovascular mortality (P = .016). Most patients
required a combination of dihydropyridine calcium channel blockers (DCCBs) plus ACEinhibitors or beta-blockers to achieve these DBP levels.
The HOPE Study investigators examined the effects of ACE inhibitors on cardiovascular
and renal disease in a diabetic subpopulation of 3577 individuals.[49] Compared with
patients taking placebo, subjects assigned to ACE inhibitor therapy experienced a 24%
risk reduction in total mortality, a 37% risk reduction in cardiovascular death, and a 22%
risk reduction in MI.
Some evidence suggests that treatment with angiotensin II receptor antagonists results
in a greater cardiovascular risk reduction in hypertensive patients compared with betablocker therapy.[50-52] Losartan Intervention For Endpoint Reduction in Hypertension
Study (LIFE) investigators randomized 9193 hypertensive patients with left ventricular
hypertrophy (LVH) to receive the angiotensin II type 1 receptor blocker losartan or the
beta-blocker atenolol.[51]
While the drugs were equally effective in reducing SBP and DBP, they had significantly
different effects on CVD outcome measures. After an average clinical follow-up of 4.8
years, patients in the losartan group were afforded a 13%reduction in the risk of
cardiovascular death, MI, or stroke (P = .021) and ; the risk reduction in fatal/nonfatal
stroke in the losartan group vs the atenolol group was 25% (P = .001). Of interest,
losartan therapy was associated with a 25% risk reduction in the development of newonset diabetes compared with atenolol therapy (P = .001) In addition, patients in the
losartan group experienced approximately a 2-fold greater ECG-LVH regression
compared with those in the atenolol group. In a subset of 1195 patients with diabetes,
there was a 39% risk reduction in all-cause mortality (P = .02) compared with patients
treated with atenolol.[52]
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Diet, Weight Loss and CVD
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Lifestyle modifications (Table 2) have also been shown to be effective methods of
reducing blood pressure and other cardiovascular risk factors.[53] Even when lifestyle
changes are not sufficient to adequately control hypertension, patients who adopt these
changes may require fewer and lower doses of antihypertensive medications. [44,45] In
addition, these healthy habits may actually prevent hypertension in the normotensive
population.[54-58]
Table 2. Recommended Lifestyle Modifications
Lose weight if overweight
Limit alcohol intake to no more than 1 oz ethanol (eg, 24 oz beer, 10 oz wine, or 2 oz of
100-proof whiskey) per day, or 0.5 oz ethanol per day for women and lighter-weight
people
Increase aerobic physical activity to 30-45 minutes per day, most days of the week
Reduce sodium intake to no more than 100 mmol per day (2.4 g sodium or 6 g sodium
chloride)
Maintain adequate intake of dietary potassium at a level of approximately 90 mmol per
day
Maintain adequate intake of dietary calcium and magnesium
Stop smoking
Reduce intake of dietary saturated fat and cholesterol
Modified from: Joint National Committee on Prevention, Detection, Evaluation, and
Treatment of High Blood Pressure. The Sixth Report of the Joint National Committee on
Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. NIH
Publication No. 98-4080, November 1997.
Excess body weight is an important modifiable risk factor in hypertension. Body mass
index values >/= 27 and waist circumferences >/= 34 inches in females or >/= 39 inches
in males are all associated with increased risk of hypertension, dyslipidemia, diabetes,
and CHD mortality.[59]
Weight reduction of as little as 10 pounds (4.5 kg) has been shown to reduce blood
pressure in a large percentage of overweight people with hypertension. [59-64]
Furthermore, weight loss can boost the effect of concurrent antihypertensive agents and
reduce concomitant CVD risk factors.[62] As a result, guidelines recommend that every
overweight hypertensive patient be placed on a custom weight-loss program.[1] Aerobic
activity coupled with a low-fat, low-cholesterol hypocaloric diet with restricted sodium is
integral to any weight loss plan.
Dyslipidemia
The link between increasing LDL cholesterol and CHD risk is well established. In
addition, clinical trials clearly show that LDL-lowering therapy reduces the risk for CHD.
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ATP III places increased importance on primary prevention of dyslipidemia in patients
without established CHD who have multiple CVD risk factors.[2]
The characteristic CVD risk factors of the metabolic syndrome combine to enhance risk
for CHD at any given LDL cholesterol level.[18] Thus, after appropriate control of LDL
cholesterol, ATP III recommends therapeutic lifestyle changes, including dietary
changes combined with regular exercise and weight management, as first-line therapies
for all risk factors associated with the metabolic syndrome. The guidelines recommend
a diet low in saturated fat and cholesterol. Individuals with significantly elevated LDL
levels are advised to increase their fiber intake and to add plant sterol or stanol to their
diet.
Sedentary lifestyle is a major risk factor for CVD that boosts the risk of the lipid and
nonlipid risk factors in the metabolic syndrome. Regular physical activity reduces VLDL
levels, raises HDL cholesterol, and in some persons, lowers LDL levels.[61] As a result,
regular physical activity should be a standard part of any cholesterol management
program.
In addition to LDL-cholesterol levels, ATP III recommends that clinicians consider the
specifics of metabolic syndrome-associated dyslipidemia (ie, elevated triglycerides and
low HDL-cholesterol levels) when constructing lipid-lowering treatment plans. Recent
analyses indicate that triglycerides are an independent risk factor for CHD. [65-68] In
practice, elevated serum triglycerides are most often observed in persons with the
metabolic syndrome. Since they are the most accessible indicator of atherogenic
lipoproteins, clinicians can monitor VLDL cholesterol levels during intervention. Thus,
VLDL cholesterol can be a target of cholesterol-lowering therapy. According to ATP III,
the sum of LDL+VLDL cholesterol is a secondary target of therapy in persons with high
triglycerides.
Analysis of data from 4S indicates that patients with impaired fasting glucose levels and
those with diabetes can benefit from cholesterol-lowering drugs. Haffner and
colleagues[41] retrospectively analyzed the effect of simvastatin therapy on CHD in
patients with normal fasting glucose (n = 3237), impaired fasting glucose (IFG; n = 678),
and diabetes mellitus (n = 483). Patients with IFG and diabetes treated with simvastatin
experienced significant reductions in the risk of major coronary events,
revascularizations, and total coronary mortality.
Treatment strategies for hypertriglyceridemia vary depending upon the cause and
severity. For high-risk patients, drug therapy is indicated to reduce elevated
triglycerides. Weight loss and increased physical activity are considered essential
components of achieving all non-HDL cholesterol goals.
Low HDL cholesterol, defined by ATP III as < 40 mg/dL, has also been shown to be a
strong independent predictor of CHD.[69-73] Some evidence suggests that lipid-lowering
drugs such as fibrates can reduce the risk of stroke in patients with coronary heart
disease and low levels of HDL cholesterol. For example, in the Veterans Affairs HDL
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Intervention Trial (VA-HIT), more than 2500 men were randomized to gemfibrozil or
placebo and were followed up for 5 years.[69,70] There was a high prevalence of the
metabolic syndrome (obesity, type 2 diabetes, and hyperinsulinemia) in the study group.
Patients in the gemfibrozil group experienced a relative risk reduction of 31% (95% CI,
2% to 52%, P =.036).
However, due to insufficient evidence, the ATP III does not specify a goal for boosting
HDL levels. Thus, in patients with the metabolic syndrome, the primary target of therapy
is LDL cholesterol. Once appropriate LDL cholesterol levels have been achieved, weight
reduction and increased exercise should be strongly recommended. Fibrates or nicotinic
acid to increase HDL can be considered in patients with low HDL in combination with
elevated triglycerides.
Hypercoagulability
Insulin-resistant patients have been shown to have high levels of circulating
plasminogen activator inhibitor type 1 (PAI-1), a protein that inhibits fibrinolysis.[74-77]
Along with increases of Factor VII, a coagulation factor found in hypertriglyceridemic
patients, PAI-1 is thought to play an important role in the hypercoagulability state so
often observed in patients with the metabolic syndrome. In addition, some studies show
that PAI-1 levels are associated with an increased risk of coronary artery disease.
Recently, Festa and colleagues[75] examined the concentrations of C-reactive protein
(CRP), fibrinogen, and PAI-1 in 1047 nondiabetic subjects. The 144 patients who had
developed diabetes at follow-up had higher initial levels of fibrinogen and PAI-1 than did
subjects who remained diabetes-free. After adjusting for BMI and insulin, only PAI-1
remained significantly related to incident type 2 diabetes (P = .002). Thus, PAI-1 level
may be helpful in determining the risk of diabetes and, by extension, the risk of CHD, in
patients with the metabolic syndrome.
Antiplatelet therapy has been shown in numerous multicenter interventional trials to
reduce the rate of cardiovascular events in both nondiabetic and diabetic patients. [78-82]
In 1994, results of the first publication of the Antiplatelet Trialists Collaboration showed
a risk reduction of 15% to 20% of MI in diabetic patients.[80] Results of the HOT trial
showed aspirin therapy similarly reduced the risk of MI.[8,48] Other antiplatelet therapies
such as glycoprotein (GP) IIb/IIIa receptor inhibitors, fibrinogen, and adenosine
diphosphate receptor antagonists have also proven effective at reducing the risk of
cardiovascular events in diabetic and nondiabetic patients.
Impaired endothelial function is thought to play an integral role in the increased risk of
CVD associated with insulin resistance. Studies show that patients with insulin
resistance have abnormal nitric oxide-mediated endothelium-dependent vasodilatation
and elevated plasma levels of PAI-1 and endothelin 1, as well as monocyte
adhesiveness.[83]
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Stühlinger and colleagues[84] recently studied the relationship between tissue insulin
sensitivity and plasma levels of the nitric oxide synthase (NOS) inhibitor asymmetric
dimethylarginine (ADMA), whose elevated levels had previously been shown to be
associated with an increased risk of CVD.[85] Sixty-four healthy individuals without
diabetes (48 with normal blood pressure and 16 with hypertension) were enrolled in the
cross-sectional study. Seven insulin-resistant hypertensive patients were studied before
and after administration of the insulin-sensitizing agent rosiglitazone.
Plasma ADMA concentrations were positively associated with insulin resistance in
nondiabetic, normotensive subjects (P < .001). In addition, ADMA levels were positively
correlated with fasting triglyceride levels, but not with LDL cholesterol levels. Of interest,
plasma ADMA concentrations increased in insulin-resistant subjects independent of
hypertension. Rosiglitazone treatment improved insulin and significantly reduced mean
plasma ADMA concentrations in the 7 patients studied.
Lifestyle Modification: The Key to Weight Loss
Thanks in part to a greater understanding and awareness of the pivotal role obesity
plays in CVD and in the metabolic syndrome, interventions have shifted away from
weight management alone to a comprehensive program of lifestyle modification.[12,86] It
is now recognized that overweight and obesity are the result of intricate interactions
between social, behavioral, cultural, physiologic, metabolic, and genetic factors in
association with a sedentary lifestyle and high-fat, energy-dense diet. Thus, lifestyle
modification involving changes in dietary intake, physical activity, and behavior must all
be part of the therapy regimen. The current gold standard for treating obesity involves
an individualized combination of all of these components, with the addition of
medication in some cases.
Successful weight loss promotion in clinical practice is often challenging, if not
frustrating. Recent clinical trials, nevertheless, show that modest yet meaningful and
sustainable weight losses of 5% to 10% of basal body weight are achievable. In
addition, a growing body of research supports the value of identifying and treating
obesity in patients with the metabolic syndrome.
Identifying High-Risk Patients
According to the NHLBI, overweight is defined as a BMI of 25.0-29.9 kg/m2, while
obesity is defined as a BMI of >/= 30.[12] Individuals with a BMI of 25-30 kg/m2 and
comorbidities of obesity should be treated with diet, exercise, and behavior therapy. [12]
For cases in which diet, exercise, and behavior therapy fail to achieve desired goals,
medication can be considered. Pharmacotherapy is indicated in patients with a BMI of
30 kg/m2 or a patient with a BMI of 27-30 kg/m2 with comorbidities such as
hypertension, diabetes, hyperlipidemia, sleep apnea, or arthritis.
Diabetes Prevention via Weight Loss
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The Diabetes Prevention Program (DPP) was the first major clinical trial to show that
diet and exercise delay the development of type 2 diabetes in a cohort of overweight
patients with IGT.[87-91] Subjects were randomly assigned to 1 of 3 treatment groups:
patients in 1 group were treated with intensive lifestyle intervention including diet and
exercise, with the remaining patients divided into 2 masked medication treatment
groups combining either metformin or placebo with standard diet and exercise
recommendations.
Subjects in the intensive-lifestyle group achieved a 58% reduction in their risk of
developing type 2 diabetes. These subjects engaged in 30 minutes per day of moderate
exercise and achieved a modest 7% average weight loss in the first year; they
maintained an average 5% weight loss for the duration of the trial. Participants
randomized to metformin therapy and given instruction on diet and exercise reduced
their risk of developing type 2 diabetes by 31%. Further analysis of DPP data will look at
the effect of these interventions on risk factors for CVD.
The Da Qing Study and the Finnish Diabetes Prevention Study had similar outcomes. [9295] Both groups studied the role of intensive lifestyle modification in preventing the
progression from IGT to type 2 diabetes. Finnish researchers randomly assigned 523
overweight subjects with IGT to the intervention or control group. The goals of the
intervention were a weight reduction of >/= 5%, a total fat intake of < 30% of total
energy, saturated fat intake of < 10% of energy intake, a fiber intake of > 15 g per 1000
calories, and moderate exercise of >/= 30 minutes per day.
The mean weight loss at the end of the first and second years was significantly greater
in the lifestyle intervention group compared with the control group. By the end of year 2,
the intervention group had lost a mean of 3.4 kg vs 0.8 kg in the control group. The risk
of diabetes was reduced by 58% in the intervention group compared with the control
group.
These and a host of earlier studies show that a modest weight loss of 5% to 10% of
basal body weight is associated with significant reductions in blood pressure, lipid
levels, and mortality.[95-100] The benefits of weight loss include improved lipid profile,
reduced blood pressure, better glycemic control, reduced left ventricular mass, and an
overall improvement in CVD risk profile.[95-102] Thus, clinicians and patients should make
efforts to embrace this achievable weight loss goal.
Which Diets Work?
While popular "fad" diets such as high-protein or low-carbohydrate diets often focus on
manipulating specific food groups, healthy sustained weight loss is, in theory, much
simpler. Body weight is determined by the relationship between calories consumed and
calories expended. Thus, depending on an individual's weight, subtracting 500 to 1000
kcal/day from the diet is an integral part of any weight-loss program (Table 3).[12]
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The quality, not just the quantity, of calories is important in weight loss and disease
prevention. Fat intake, particularly saturated fat, should comprise < /= 30% of total
calories. Patients should be counseled that reducing the percentage of dietary fat alone
would not produce weight loss unless total calories are also reduced. Frequent followup and communication with the patients helps promote weight loss and maintenance.
Physicians should also consider referring patients to registered dieticians for care and to
organizations such as the American Heart Association (AHA) for further information and
support.
A more structured diet may be appropriate and effective for some patients. During the
course of 1 week, a patient must face 21 breakfasts, 21 lunches, and 21 dinners. For
some individuals, relying on liquid meal replacements or strict meals may help in weight
loss and weight maintenance. Patients in the DPP were encouraged to refer to the Food
Guide Pyramid and the National Cholesterol Education Program Step 1 diet in order to
adhere to a low-calorie, low-fat diet.[87,103,104]
Exercise: How Much? What Type?
How much and what kind of exercise is needed? The Surgeon General, CDC, and AHA
recommend a regular program of moderate-to-vigorous intense physical activity for an
accumulated time of >/= 30 minutes a day.[61] Resistance training for 20-30 minutes
twice a week is also strongly recommended, particularly for women, as it can aid in the
prevention and treatment of osteoporosis.
It is important to stress that reaping the benefits of exercise does not require a personal
trainer or marathon running. Lifestyle activities such as taking the stairs instead of the
elevator, raking leaves, doing housework, and brisk walking are all modes of physical
activity that should be encouraged. A busy person need not exercise for 30 minutes at a
time -- accruing three 10-minute segments is also beneficial.
Can Physicians Really Help to Modify Behavior?
One of the greatest challenges in treating overweight and obese patients is helping
them set realistic, yet clinically meaningful weight loss goals of a 5% to 10% reduction in
initial weight.[105-109] By focusing on clinical outcomes such as improved cholesterol
levels, blood pressure, or self-esteem, clinicians can reinforce the importance of even
modest weight losses. Furthermore, by making it clear to patients at the outset that they
can expect to lose an average of 10% of their initial weight after 6 months will help
temper lofty and unlikely weight-loss goals.
The successful lifestyle intervention program employed in the DPP[87] relied on
individualized one-on-one counseling detailing the basics of diet, exercise, and behavior
modification. Guidelines recommended that case managers meet with study participants
weekly for 20 of 24 weeks, since studies show that more frequent patient contact
promotes weight loss.
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Physicians should expect patients to falter in their efforts to employ lifestyle
modifications. Encouraging individuals to set specific, realistic goals for positive change
can help promote adherence. Close monitoring of patient weight-loss goals is also
important. In addition, referring patients to weight control or wellness clinics as well as
to dieticians and nutritionists can help promote adherence to lifestyle modification.
Pharmacotherapy: When Diet and Exercise Aren't Enough
When adequate weight reduction is not achieved by lifestyle changes, weight-loss drugs
can be considered. Even when pharmacologic intervention is deemed appropriate,
lifestyle modification can improve the efficacy of available agents.[110,111]
Weight-loss drugs are recommended in individuals with a BMI >/= 30 kg/m 2 and no
concomitant obesity-related factors or disease.[111] Patients who have serious risk
factors and diseases such as hypertension, dyslipidemia, CHD, type 2 diabetes, or
sleep apnea should be considered for pharmacotherapy at a BMI of 27-29.9 kg/m2.
Currently, 2 drugs are approved for long-term treatment of obesity: orlistat and
sibutramine.
Orlistat
Individuals who need help in keeping dietary fat intake to 30% of calories may benefit
from the lipase inhibitor orlistat. Orlistat inhibits the action of intestinal lipase, thus
reducing dietary fat absorption by up to 30%. In clinical trials, it produces approximately
5% to 10% loss of initial body weight.[112,113] When prescribed in combination with a
weight-maintenance diet, orlistat results in better maintenance of weight loss compared
with placebo.[113]
Because orlistat reduces absorption of fat-soluble vitamins (especially vitamin D) and
beta-carotene, vitamin supplementation is recommended during therapy. The adverse
effects of orlistat are primarily gastrointestinal and are intensified by consumption of
high-fat foods.
In obese people with the metabolic syndrome, orlistat therapy resulted in weight loss
associated with a reduction in plasma insulin and CHD risk factors.[114-116] Pooled data
from 3 randomized, double-blind, placebo-controlled trials showed that orlistat combined
with dietary interventions led to a greater rate of glycemic normalization compared with
the placebo group.[115]
Sibutramine
For patients who seem to be having trouble with satiety, sibutramine might help promote
weight loss. Sibutramine can help reduce appetite and lessen the preoccupation with
food, giving patients a better chance at complying with dietary guidelines. The most
frequently reported adverse effects include dry mouth, anorexia, headache, insomnia,
and constipation.
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Sibutramine inhibits the reuptake of norepinephrine and serotonin, and, to a lesser
extent, dopamine. In clinical trials, it produces a dose-dependent 5% to 10% decrease
in body weight. Treatment with sibutramine accompanied by dietary guidance has been
shown to result in significantly greater weight loss than dietary advice alone.[117]
Weight loss with sibutramine has also been shown to be associated with favorable
changes in CVD risk factors, including plasma lipids, uric acid, and glucose.[118-123]
James and colleagues[124] conducted a multicenter, double-blind trial on the
effectiveness of sibutramine in maintaining weight loss over 2 years. In the first step of
the study, 605 obese patients were randomized to a hypocaloric diet plus 10 mg/day
sibutramine or to diet plus placebo. Next, the 467 patients who had lost more than 5%
of their basal body weight were randomized to 10 mg/day sibutramine or placebo for an
additional 18months.
Forty-two percent of the sibutramine group and 50% of the placebo group dropped out
of the study. Of those who remained, 43% of sibutramine-treated individuals maintained
>/= 80% of their original weight loss over 2 years compared with 16% of the placebo
group (P < .001). Patients had substantial decreases in the levels of triglycerides, VLDL
cholesterol, insulin, C peptide, and uric acid. Only patients in the sibutramine group
sustained these changes over 2 years. In addition, HDL cholesterol concentrations rose
significantly more in the second year in the sibutramine group (20.7%) compared with
the placebo group (11.7%).
In this and other studies, sibutramine treatment was associated with small mean
increases in blood pressure and heart rate. Thus, it is recommended that blood
pressure and heart rate be assessed before prescribing or increasing the dose of
sibutramine.
Phentermine
While it is only approved for 3-month usage, phentermine remains the most popular
weight loss drug. Clinical trials have shown that treatment with phentermine results in a
5% to 15% weight loss in 60% of patients if given daily or intermittently.[125-127]
Phentermine is cheaper than sibutramine and orlistat. Its biggest drawbacks are that it
is indicated only for short-term treatment and tolerance often develops. Like all
noradrenaline reuptake inhibitors, phentermine's side effects include dry mouth,
constipation, sleep disturbance, and increased blood pressure. When taken in
conjunction with a hypocaloric diet, more weight loss is seen.
Putting It All Together for the Best Results
Clinicians should prescribe weight-loss-promoting drugs in concert with diet, exercise,
and behavior modification. A recent study demonstrates the efficacy of this approach.
Wadden and colleagues[111] compared the effects of 3 approaches to weight loss. Fiftythree women were randomized to 1 of 3 groups: sibutramine alone; sibutramine and
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lifestyle modification including a 1200-1500 kcal/day diet (drug-lifestyle); or sibutramine,
lifestyle modification, and a portion-controlled diet (1000 kcal/day) diet for the first 4
months (drug-lifestyle-diet).
At month 12, patients treated with the drug alone lost a mean of 4.1% of their initial
body weight; patients in the drug-lifestyle group lost a mean of 10.8% of their initial body
weight; and patients in the drug-lifestyle-diet group lost a mean of 16.5% of their initial
body weight. Women in both lifestyle intervention groups achieved a greater percentage
of their expected weight loss than those in the drug-alone group (P < .05). Significant
reductions in triglyceride and LDL levels were also observed at 12 months. Thus, the
addition of group lifestyle modification to the pharmacologic management of obesity
significantly improved weight loss.
Surgical Interventions for Weight Loss
Bariatric surgery can be considered in patients with morbid obesity, defined as a BMI of
>/= 40 kg/m2, or in individuals who exceed their ideal body weight by >/= 100
pounds.[118,119,128] Patients with a BMI between 35 and 40, or those who exceed their
ideal body weight by >/= 85 pounds must have associated comorbidities to warrant the
risk associated with bariatric surgery.
The 2 widest classifications of bariatric surgery include vertical banded gastroplasty
(VBG) and Roux-en-Y gastric bypass (GBP).[119,120] Studies show that VBG results in a
weight loss of 25% to 50% in 50% to 80% of patients 5 years after surgery.[121,122] GBP,
the most widely performed procedure, is considered the "gold standard" in bariatric
surgery. It achieves a more sustained weight loss compared with that resulting from
VBG: a 40% to 85% decrease in excess body weight in > 90% of patients.[123,129] In
most cases, weight loss is maintained.[130,131]
Cardiovascular Disease Trials: Where Are the Data on Obesity?
Over the last 3 decades, vast numbers of clinical trials have led to an explosion of
knowledge affecting the way cardiovascular disease is treated and prevented. The
increasing use of ACE inhibitors, beta-blockers, and statins in ever healthier patient
populations are excellent examples of the cumulative effect of small and large trials on
clinical practice.[132-140] This research has identified strategies to prolong survival,
reduce morbidity, and improve QOL in patients with CVD.
Small clinical trials are useful for examining physiologic mechanisms and determining
the effects of drugs on cardiovascular symptoms. These trials demonstrate beneficial
effects on surrogate outcomes such as changes in exercise time or changes in
symptoms. Yet it is always important to keep in mind that surrogate outcomes are just
that -- surrogate. Thus, beneficial effects on surrogate outcomes don't necessarily
translate into beneficial effects on clinical events or reductions in mortality and
morbidity. Nevertheless, data from small clinical trials are vital to the process of
designing larger trials to assess drug effects on clinical events.
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Large clinical trials typically examine mortality and morbidity events. Because of the
large sample size, these trials can detect even moderate treatment effects. It is
important to note that the progression of CVD involves a complex set of interrelated
factors all contributing to the clinical condition. Thus, even when a therapy has been
shown to positively affect clinical outcomes, the nature of the disease process limits the
impact of the therapy. As such, any particular therapy can only be expected to have a
moderate effect on the clinical picture of disease.
Obesity and CVD: Surrogate Data vs Cardiovascular Clinical Outcomes
The relationship between increasing body mass index and CVD risk factors has been
well established. For example, a 10-kg weight gain produces an approximate 3-mm rise
in systolic blood pressure and a 2-mm rise in diastolic blood pressure, and increases
the risk of CHD and stroke. Obesity is also an independent predictor of CHD,
congestive heart failure, and cardiovascular morbidity and mortality. Furthermore,
obesity significantly and independently correlates with increases in LV mass. Indeed,
surrogate data show that weight loss leads to improvements in dyslipidemia,
hypertension, insulin resistance, and abdominal obesity and LV mass.[141-146]
These improvements suggest that weight loss should also beneficially affect clinical
outcomes. Unfortunately, surrogate outcomes don't always predict clinical outcomes. To
date, there have been no large, prospective, randomized, controlled trials looking at the
effects of weight loss on cardiovascular clinical outcomes. There are, in fact, some
observational studies or meta-analyses suggesting that weight loss or fluctuations may
actually increase cardiovascular morbidity and mortality.[147-149] Only large, long-term,
randomized trials will answer this important question.
References
1. Joint National Committee on Prevention, Detection, Evaluation, and Treatment of
High Blood Pressure. The Sixth Report of the Joint National Committee on
Prevention, Detection, Evaluation, and Treatment of High Blood Pressure.
National Institutes of Health. National Heart, Lung, and Blood Institute. National
High Blood Pressure Education Program. NIH Publication No. 98-4080;
November 1997.
2. Third Report of the Expert Panel on Detection, Evaluation, and Treatment of High
Blood Cholesterol in Adults (Adult Treatment Panel III). National Cholesterol
Education Program. National Heart, Lung, and Blood Institute. National Institutes
of Health. NIH Publication No. 01-3670; May 2001.
3. Lamarche B, Tchernof A, Mauriege P, et al. Fasting insulin and apolipoprotein B
levels and low-density lipoprotein particle size as risk factors for ischemic heart
disease. JAMA. 1998;279:1955-1961.
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4. Lamarche B, Tchernof A, Moorjani S, et al. Small, dense low-density lipoprotein
particles as a predictor of the risk of ischemic heart disease in men. Prospective
results from the Quebec Cardiovascular Study. Circulation. 1997;95:69-75.
5. Kannel WB. Potency of vascular risk factors as the basis for antihypertensive
therapy. Eur Heart J. 1992;13(suppl G):34-42.
6. Kannel WB. Blood pressure as a cardiovascular risk factor. JAMA.
1996;275:1571-1576.
7. Neaton JD, Wentworth D, for the Multiple Risk Factor Intervention Trial Research
Group. Serum cholesterol, blood pressure, cigarette smoking, and death from
coronary heart disease. Overall findings and differences by age for 316 099 white
men. Arch Intern Med. 1992;152:56-64.
8. Reaven GM, Lithell H, Landsberg L. Hypertension and associated metabolic
abnormalities -- the role of insulin resistance and the sympathoadrenal system. N
Engl J Med. 1996;334:374-381.
9. Cohn JN. Arteries, myocardium, blood pressure and cardiovascular risk: towards
a revised definition of hypertension. J Hypertens. 1998;16(12 pt 2):2117-2124.
10. National Center for Health Statistics, Centers for Disease Control and
Prevention. Prevalence of overweight and obesity among adults: United States.
Hyattsville, Md; 1999.
11. World Health Organization. Definition, Diagnosis, and Classification of Diabetes
Mellitus and Its Complications. Department of Noncommunicable Diseases.
Geneva, Switzerland; 1999.
12. National Institutes of Health, National Heart Lung and Blood Institute. Clinical
Guidelines on the Identification, Evaluation, and Treatment of Overweight and
Obesity in Adults: The Evidence Report. United States Department of Health and
Human Services, Public Health Service, NIH, NHLBI; 1998.
13. United States Department of Health and Human Services. The Surgeon
General's Call to Action to Prevent and Decrease Overweight and Obesity.
Rockville, Md: US Department of Health and Human Services, Public Health
Service, Office of the Surgeon General; 2001.
14. Wolf A, Colditz G. Current estimates of the economic cost of obesity in the United
States. Obes Res. 1998;6:97-106.
15. Ford ES, Williamson DF, Liu S. Weight change and diabetes incidence: findings
from a national cohort of US adults. Am J Epidemiol. 1997;146:214-222.
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Florida Heart CPR*
Diet, Weight Loss and CVD Assessment
1. Traditional CVD risk factors include:
a. Hypertension
b. Dyslipidemia
c. Cigarette smoking
d. All of the above
2. CVD is a progression that begins and continues through a complex interaction
between ______.
a. Genetics and diet
b. Genetics and the environment
c. Exercise and the environment
d. Diet and exercise
3. _____ tends to cluster in patients with other cardiovascular risk factors, such as
abnormalities of glucose, insulin, and lipoprotein metabolism.
a. Hypotension
b. Hypertension
c. Obesity
d. Diabetes
4. _______ patients are more likely to be obese, to smoke cigarettes, and to have a
family history of CVD compared with their normal counterparts.
a. Elderly
b. Overweight
c. Hypertensive
d. All
5. At its essence, the ______ is a cluster of characteristics that together increase
the risk of diabetes and CHD in addition to numerous other health problems.
a. Insulin syndrome
b. Digestion syndrome
c. Metabolic syndrome
d. Dyslipidemia syndrome
6. _______, often the first clinical marker of the metabolic syndrome, involves an
overproduction of glucose by the liver, impaired peripheral glucose utilization,
and an increased breakdown of fat, or lipolysis, leading to elevated levels of free
fatty acids.
a. Glucose resistance
b. Insulin resistance
c. Lipid resistance
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d. Glucagon resistance
7. Hypertension is defined as systolic blood pressure (SBP) of > /= ___ mm Hg,
diastolic blood pressure (DBP) of >/= ____ mm Hg, or the use of
antihypertensive drugs.
a. 150; 90
b. 140; 90
c. 130; 80
d. 130; 90
8. _______ in DBP and SBP have been shown to be directly and continuously
associated with increases in CVD risk.
a. Increases
b. Decreases
c. Rapid changes
d. Any of the above
9. ________ reduces VLDL levels, raises HDL cholesterol, and in some persons,
lowers LDL levels.[61] As a result, it should be a standard part of any cholesterol
management program.
a. Eating less
b. Regular dieting
c. Regular physical activity
d. Prescription drug use
10. Impaired ________ function is thought to play an integral role in the increased
risk of CVD associated with insulin resistance.
a. Epithelial
b. Endothelial
c. Tunica media
d. Tunica externa
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