Download AGA Technical Review on Obesity

GASTROENTEROLOGY 2002;123:882–932
AGA Technical Review on Obesity
This literature review and the recommendations therein were prepared for the American Gastroenterological Association Clinical
Practice Committee. The paper was approved by the Committee on March 3, 2002, and by the AGA Governing Board on
May 19, 2002.
besity is a chronic and stigmatizing disease that has
become a major health problem in most industrialized countries because of its high prevalence, causal
relationship with serious medical illnesses, and economic
impact. In the United States, it is estimated that obesity
is responsible for approximately 300,000 deaths per
year,1 and that the direct (medical expenses) and indirect
(value of lost productivity) costs of obesity exceed $100
billion per year.2 Obesity has particular relevance for
gastroenterologists because (1) obesity causes gastrointestinal diseases, including cholelithiasis, pancreatitis,
and liver disease; (2) patients who have had obesity
surgery may need a gastroenterologist to evaluate and
treat postoperative intestinal complications; and (3) the
gastrointestinal tract is a viable target for current and
future obesity therapies that affect nutrient absorption or
gut hormones involved in appetite regulation.
This review provides gastroenterologists with a comprehensive evaluation of the important clinical issues in
adult obesity, including prevalence, etiology, physiology,
pathophysiology, medical complications, metabolic and
medical effects of weight loss, treatment options, and
treatment guidelines. The information reviewed by the
authors was identified by a literature search of Index
Medicus between 1966 (volume 1) and January 2002, a
hand search of individual journals that focus on obesity,
and identifying papers from the reference lists of research
and review articles.
O
Definition of Obesity
Body Fat and Body Mass Index
Obesity can be defined as an excessive amount of
body fat, which increases the risk of medical illness and
premature death. Accurate assessment of body fat mass
requires the use of sophisticated and expensive technologies that are not readily available to most physicians.
Moreover, the determination of healthy and unhealthy
amounts of fat mass is complicated because the amount
of body fat that causes medical complications depends on
sex, age, fat distribution, weight (fat) gain since early
adulthood, level of fitness, genetic factors, and concomitant disease risk factors. Recently, the World Health
Organization,3 the National Institutes of Health (NIH),4
Healthy People 2010,5 and the 2000 Dietary Guidelines
for Americans6 proposed guidelines for classifying
weight status by body mass index (BMI) (Table 1). BMI
represents the relationship between weight and height
and is calculated as weight (in kg) divided by height (in
m2) or as weight (in pounds) times 704 divided by height
(in inches2). Although, BMI usually is correlated closely
with percent body fat mass in a curvilinear fashion,7
some persons with an “obese” BMI may have a normal
amount of body fat and a large muscle mass, while others
with a “normal” BMI may have excess adiposity and
reduced muscle mass.
BMI and Mortality
The BMI classification scheme for weight status is
based on data obtained from large epidemiological studies that evaluated the relationship between BMI and
mortality8 –10 and provides a mechanism for identifying
patients who are at increased risk for having or developing adiposity-related complications. Both men and
women who have a BMI ⱖ30 kg/m2 are considered obese
and are generally at higher risk for adverse health events
than are those who are considered overweight (BMI
between 25.0 and 29.9 kg/m2) (Figure 1). It could be
argued that these cutoff values, which are based on
BMI-mortality relationships, are too high because the
prevalence of obesity-related diseases, such as diabetes,
Abbreviations used in this paper: BDD, balanced-deficit diet; BMI,
body mass index; CHD, coronary heart disease; FFM, fat-free mass;
GBP, gastric bypass procedure; GERD, gastroesophageal reflux disease; HDL, high-density lipoprotein; IIH, idiopathic intracranial hypertension; JIB, jejunoileal bypass; LASGB, laparoscopically inserted adjustable silicone gastric band; LCDs, low-calorie diets; LDL, low-density
lipoprotein; LES, lower esophageal sphincter; NASH, nonalcoholic steatohepatitis; NAFLD, nonalcoholic fatty liver disease; NHLBI, National
Heart, Lung and Blood Institute; PAI-1, plasminogen activator inhibitor
1; REE, resting energy expenditure; SF-36, Study Short-Form Health
Survey; SOS, Swedish Obese Subjects; TEE, total energy expenditure;
TOHP II, Trials of Hypertension Prevention Phase II; UGI, upper gastrointestinal radiographic; USFDA, United States Food and Drug Administration; VBG, vertical-banded gastroplasty; VLCDs, very-low-calorie
diets.
© 2002 by the American Gastroenterological Association
0016-5085/02/$35.00
doi:10.1053/gast.2002.35514
September 2002
AMERICAN GASTROENTEROLOGICAL ASSOCIATION
Table 1. BMI-associated Disease Risk
Underweight
Normal
Overweight
Obesity
Extreme obesity
Obesity class
BMI (kg/m2)
Risk
I
II
III
⬍18.5
18.5–24.9
25.0–29.9
30.0–34.9
35.0–39.9
ⱖ40.0
Increased
Normal
Increased
High
Very high
Extremely high
Additional risks: (1) waist circumference ⬎40 inches in men and ⬎35
inches in women; (2) weight gain of ⱖ5 kg since age 18 –20 years; (3)
poor aerobic fitness; and (4) Southeast Asian descent.
Data from 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. Obes Res 1998;6(Suppl 2):51S–209S.4
hypertension, and coronary artery disease, begins to increase at BMI values below 25 kg/m2. Furthermore, the
relationship between adiposity and health risk is a continuum. Classification by BMI imposes cutoff values for
risk within this continuum; this is similar to the way in
which the definition of hypertension imposes cutoff values within the continuous relationship between blood
pressure and cardiovascular disease risk. Therefore, BMI
values should be considered as one component of an
assessment of adiposity-related disease risk and not the
absolute criterion for determining clinical care.
In adults, the relative risk of death associated with
increasing BMI decreases with increasing age.11 These
data have been misinterpreted as demonstrating that
obesity is less harmful in the elderly than in young and
middle-aged adults.12 However, the absolute mortality
risk associated with an increased BMI actually increases
with age, up to the age of 75 years, because of the marked
increase in mortality with advancing age. Therefore,
from a clinical perspective, the health complications
associated with obesity increase linearly with increasing
BMI until the age of 75 years. In elderly persons, BMI
has less of an impact on mortality but possibly a greater
effect on quality of life.
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(abdominal subcutaneous and visceral fat) phenotype are
at increased risk for diabetes, hypertension, dyslipidemia,
and ischemic heart disease. Measurement of abdominal
fat content requires the use of expensive radiological
imaging techniques, so waist circumference is often used
as a surrogate marker because it has been shown to
correlate closely with abdominal fat mass.15 The Expert
Panel on the Identification, Evaluation, and Treatment of
Overweight and Obesity in Adults, convened by the
National Institutes of Health, proposed that men with a
waist circumference greater than 102 cm (40 inches) and
women with a waist circumference greater than 88 cm
(35 inches) are at increased risk for metabolic diseases.4
Although this recommendation is based on sound epidemiological and metabolic studies, it imposes cutoff
values on the continuous relationship between waist
circumference and metabolic disease risk.
Weight gain. Weight gain during adulthood is
an additional risk factor for medical complications. Data
obtained from epidemiological studies suggest that a
gain of 5 kg or more in body weight since the age of 18
to 20 years increases the risk of developing cholelithiasis,
diabetes, hypertension, and coronary heart disease (CHD)
in both men and women.16 –21 Moreover, greater weight
gain is associated with a greater risk of disease. Even lean
adults (BMI 18.5 to 24.9 kg/m2) have an increased risk
of these medical illnesses if they have gained more than
5 kg since young adulthood.
Fitness. Aerobic fitness can modify the risk of
developing diabetes or cardiovascular disease associated
with obesity. In large, prospective, epidemiological studies, Blair et al.22 found that, across a range of body
adiposity, those who were fit, defined by their maximal
BMI–Related Risk Modification
In general, the higher the BMI, the greater the
risk of adiposity-related diseases and premature mortality. However, other factors, such as fat distribution,
weight gain since young adulthood, level of fitness, and
ethnic background modify BMI-related risk (Table 1).
Fat distribution. The importance of fat distribution on health was first realized about 50 years ago,13 but
was not fully appreciated until the early 1980s.14 Compared with obese persons who have predominantly increased lower body fat (gluteal and femoral fat) phenotype, obese persons with excess upper body fat
Figure 1. Relationship between BMI and cardiovascular mortality in
302,233 adult men and women in the United States who never
smoked and had no preexisting illness. Vertical lines indicate overweight (BMI 25.0 –29.9 kg/m2) and obese (BMI ⱖ30 kg/m2) cutoff
values. (Data from Calle et al.9)
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ability to consume oxygen during exercise, had a lower
incidence of diabetes22 and cardiovascular mortality23
than those who were unfit.
Ethnicity. The cut-off values for BMI-associated
risk vary by ethnic group.24,25 For example, at the same
BMI values, Southeast Asian populations have a higher
risk of diabetes and cardiovascular disease than white
patients. In contrast, Polynesians usually have more muscle mass and less body fat than white patients at the same
BMI level.
Prevalence
In the last 20 years, the prevalence of obesity has
increased markedly in industrialized and nonindustrialized countries, and it is estimated that there are now
more than 500 million overweight and 250 million obese
adults in the world.26 Moreover, the prevalence is likely
to continue to increase.
In the United States, approximately 61% (110 million) of adults (age 20 to 74 years) are overweight or
obese.27 Data from national population surveys obtained
since 1960 (1960 –1962 National Health Examination
Survey I [NHES I], 1971–1974 National Health and
Nutrition Examination Survey I [NHANES I], 1976 –
1980 NHANES II, 1988 –1994 NHANES III, and preliminary 1999 NHANES data) have demonstrated that
the prevalence of overweight increased slightly, from
30.5% to 34.0%, whereas the prevalence of obesity (BMI
ⱖ30 kg/m2) has more than doubled, from 12.8% to
27%27,28 (Figure 2). Most of the increase in body weight
has occurred since 1980. The prevalence of obesity in the
United States increases progressively from 20 to 50 years
of age, but begins to decline after age 60 to 70. The
prevalence of obesity is particularly high in many ethnic
minority women, such as African American, Mexican
American, Native American, Pacific Islander American,
Puerto Rican, and Cuban American women. In the
United Kingdom and Europe, approximately 15% of
men and 20% of women are obese.29 Obesity also has
increased in Southeast Asia, Japan, and China; it is now
more prevalent than undernutrition in Malaysia and
occurs in more than 60% of men and 75% of women in
urban Samoa.25,29
Obesity also has increased in children and adolescents.
Data from NHANES III (1988 –1994) showed that 10%
to 15% of children and adolescents (age 6 to 17 years) in
the United States are overweight, defined as a BMI
ⱖ95th percentile for age and gender from the revised
National Center for Health Statistics growth charts.30
These values represent a doubling of the prevalence rates
of overweight reported for children and adolescents ob-
Figure 2. Age-adjusted prevalence of overweight (BMI 25.0 –29.9
kg/m2) and obesity (BMI ⱖ30 kg/m2) in adults (age 20 –74 years) in
the United States since 1960. Data obtained from 1960 –1962 NHES
I, 1971–1974 National Health and Nutrition Examination Survey I
(NHANES I), 1976 –1980 NHANES II, 1988 –1994 NHANES III, and
preliminary data from NHANES 1999. The prevalence of overweight or
obesity increased (from 43% to 61%) between NHES I (1960 –1962)
and NHANES 1999 caused by a small increase in overweight (from
30.5% to 34%) and to more than a doubling in the prevalence of
obesity (from 12.8% to 27%). (Data obtained from Flegal et al.28)
and National Center for Health Statistics, Centers for Disease Control
and Prevention web site www.cdc.gov/nchs/products/pubs/pubd/
hestats/obese/obse99.htm (accessed December 14, 2001).27
served in earlier surveys. Obesity-related diseases that
typically are seen in adults, such as type 2 diabetes
mellitus, hyperlipidemia, hypertension, orthopedic complications, sleep apnea, gallbladder disease, and nonalcoholic steatohepatitis (NASH), are now being seen with
increasing frequency in children.31 In addition, earlyonset obesity is associated with an increased chance of
being an obese adult and an increased risk of obesityrelated diseases.32–33
Pathogenesis
Energy Balance
In all persons, obesity is caused by ingesting more
energy than is expended over a long period of time. Very
small but chronic differences between energy intake and
energy expenditure can lead to large increases in body
fat. For example, ingestion of only 5% more calories than
expended could result in the accumulation of ⬃5 kg of
adipose tissue in 1 year. Ingestion of only 8 kcal per day
more than expended over 30 years could lead to an
increase in 10 kg in body weight, which is the average
amount of weight gained by American adults during the
30-year period from 25 to 55 years of age.34
Genetics and Environment
Both genetic and environmental factors contribute to body size. It has been estimated that genetic
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background can explain 40% or more of the variance in
body mass in humans.35 The genetic component of human obesity is complex and likely to involve the interaction between multiple genes. More than 250 genes,
markers, and chromosomal regions have been linked
with human obesity,35a but the clinical importance of
each association is not yet known. Several monogenic
causes of obesity have been described in humans, and
include mutations in genes for leptin,36 –38 leptin receptor,39 prohormone convertase 1,40 pro-opiomelanocortin,41 melanocortin-4 receptor,42 and SIM1.43 Although
rare, these cases have increased our understanding of the
molecular mechanisms that regulate energy balance in
humans.
The marked increase in the prevalence of obesity in the
last 20 years cannot be attributed to genetic changes and
must be a result of alterations in environmental influences. It is likely that both an increase in energy intake44
and a decline in physical activity45– 47 are responsible for
the recent epidemic of obesity. Energy consumption has
increased presumably because more meals are eaten outside the home, serving sizes are larger, there is greater
availability of convenience and snack foods, and there is
an increase in food variety and palatability. Advances in
technology have led to decreased daily physical activity
because of energy-conserving devices, sedentary work
and social activities, and motorized transportation.
Environmental impact in high-risk populations.
Persons with certain genetic backgrounds are particularly
predisposed to weight gain and obesity-related diseases
when they are exposed to a modern lifestyle. Striking
examples of the influence of environment on body weight
have been reported globally. Pima Indians living in
Arizona have experienced a dramatic change in their
lifestyle, which has led to an epidemic of obesity and
diabetes in the last 50 years.48 These Pimas now eat a
high-fat diet (50% of energy as fat) provided by government surplus commodities rather than their traditional
low-fat (15% of energy as fat) diet, and are much more
sedentary than when they lived as farmers. In contrast,
Pima Indians who live in the Sierra Madre Mountains of
Northern Mexico have been isolated from Western influences, eat a traditional Pima diet, and are physically
active as farmers and sawmill workers. The Pimas of
Mexico have a much lower incidence of obesity and
diabetes than their genetic kindred who live in Arizona.
Another example is the Aborigine population of northern
Australia. Urbanized Aborigines have a high prevalence
of type 2 diabetes mellitus and hypertriglyceridemia, and
are heavier than their typically very lean (BMI ⬍20
kg/m2) relatives who live a traditional hunter-gatherer
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lifestyle.49 In urbanized Aborigines with type 2 diabetes
and hypertriglyceridemia, short-term (7-week) reversion
to a traditional hunter-gatherer lifestyle, which entailed
a low-fat, low-energy diet of wild game, fish, and plants
and increased physical activity, produced weight loss and
marked improvement or normalization of fasting blood
glucose, insulin, and triglyceride concentrations and glucose tolerance.50 In Papua New Guinea, the prevalence of
obesity in the rural Highlands is approximately 3%,
whereas 38% of the population in urban Wanigelas is
obese.25
Early environmental factors. Environmental factors in very early life may influence subsequent body
weight and the development of metabolic abnormalities.
A series of studies have found that adult men and women
who were small for gestational age at birth, defined by a
low birthweight, low ponderal index (birthweight/
length3), or small head circumference, were more likely
to have a higher BMI, a higher waist-to-hip circumference ratio, the metabolic syndrome, and coronary artery
disease than men and women who were normal-sized at
birth.51–54 The mechanism for this observation is not
known, but it has been hypothesized that fetal undernutrition and impaired fetal development may have longterm effects on organ function.55 Nutritional factors
during infancy also may be involved in subsequent body
size. A cross-sectional survey of 13,345 children in Bavaria, Germany, found that breast-feeding during the
first year of life decreased the risk of overweight and
obesity at ages 5 and 6 years.56,57 Moreover, the protective effect of childhood breast-feeding followed a doseresponse relationship and could not be explained by
social class or lifestyle.
Influence of childhood and parental obesity.
Both childhood and parental obesity affect the risk of
obesity in adulthood. Data obtained from long-term
members of a health maintenance organization in the
state of Washington showed that the risk of being an
obese young adult (21 to 29 years of age) ranged from
8% for obese 1- and 2-year-olds without obese parents to
79% for obese 10- to 14-year-olds with at least one obese
parent.58 The probability of being an obese adult increased with increasing age and severity of obesity in
childhood. An obese child at 1 or 2 years of age who had
lean parents did not have an increased risk of obesity in
adulthood, whereas being obese after 6 years of age was
associated with more than a 50% chance of being an
obese adult. In addition, the presence of obesity in one or
both parents increased the risk of obesity in adulthood.
For example, lean children with at least one obese parent
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had a 3-fold greater risk of obesity in adulthood than did
lean children with lean parents.
Energy Metabolism
Daily total energy expenditure (TEE) is comprised of (1) resting energy expenditure (REE) (i.e.,
energy expended for normal cellular and organ function
during postabsorptive resting conditions; approximately
70% of TEE); (2) thermic effect of food (i.e., the increase
in energy expenditure associated with digestion, absorption, and increased sympathetic nervous system activity
after eating a meal; approximately 10% of TEE); and (3)
energy expended in physical activity (i.e., energy cost of
volitional mechanical work, such as exercise and daily
activities, and nonvolitional activity, such as fidgeting,
spontaneous muscle contractions, and maintaining posture; approximately 20% of TEE). The resting energy
requirements of specific tissues differ dramatically (Table
2). Organs that function continuously, such as the liver,
gut, brain, kidney, and heart, have the highest energy
requirements per gram of tissue. In a lean adult, these
organs account for approximately 75% of the resting
metabolic rate, although they constitute only 10% of
total body weight. In contrast, resting skeletal muscle
consumes approximately 20% of resting metabolic rate
but represents approximately 40% of body weight, and
adipose tissue consumes less than 5% of resting metabolic rate but usually accounts for more than 20% of
body weight.
The possibility that defects in energy metabolism are
associated with obesity has been carefully evaluated in
cross-sectional studies. REE is typically greater in obese
than in lean individuals who are the same height because
of increased lean, as well as adipose, tissue cell masses in
Table 2. Resting Energy Requirements of a Man Weighing
70 kg
Tissue mass
Liver
Brain
Kidneys
Heart
Gut
Skeletal muscle
Adipose tissue
Daily energy
consumption
g
% body
weight
kcal/g
tissue
kcal
% REE
1550
1400
300
300
2000
28,000
15,000
2.2
2.0
0.4
0.4
3.0
40.0
21.0
0.28
0.30
1.27
0.80
0.15
0.014
0.005
445
420
360
235
300
400
80
19
18
15
10
13
18
4
Data from Klein S, Jeejeebhoy K. The malnourished patient: nutritional assessment and management. In: Feldman M, Friedman LS,
Sleisenger MH, eds. Gastrointestinal and Liver disease. Philadelphia,
Saunders, 2002:266.
obese persons.59 Studies in obese and lean volunteers
matched for either lean body mass or fat mass suggest
that increased adiposity in obese subjects is associated
with a small (⬃75 kcal per day) but possibly important
reduction in the thermic effect of food,60 which may be
related to insulin resistance and blunted sympathetic
nervous system activity associated with obesity.61 Obese
persons require the same amount of energy as lean persons to perform the same amount of work when body
weight is supported.62 Moreover, obese persons expend
more energy than lean persons during weight-bearing
activities because of the increased work involved in carrying more weight. However, it is not known whether
obese adults expend less total energy on daily physical
activity because they are less active than lean persons.
Two comprehensive studies performed in children found
that sleeping metabolic rate, REE, energy expenditure of
physical activity, and daily TEE were the same in lean
and obese children after adjusting for differences in body
composition.63,64 In summary, the results from a large
number of studies suggest that obese persons do not have
obvious abnormalities in any of the components of energy metabolism. In fact, defects in REE or TEE have not
even been found in “diet-resistant” patients who fail to
lose weight despite claiming strict adherence to a lowcalorie diet.65,66 These patients unknowingly underestimate their food intake and may consume twice as many
calories as recorded in daily food records.
Although significant abnormalities in energy metabolism have not been found in adults or children who are
already obese, it is still possible that inherent alterations
in energy expenditure contribute to the pathogenesis of
human obesity. However, establishing a causal relationship between energy expenditure and subsequent obesity
is difficult because measurement of energy metabolism
represents a brief “snapshot” in time, which may not
capture abnormalities that occur during specific stages of
life. In addition, the ability to detect small, but possibly
clinically important, chronic defects in metabolic rate is
limited by currently available research technology.
Nonetheless, most, but not all, studies do not support
the notion that a defect in metabolic rate predisposes to
obesity. One longitudinal study in children found that
daily TEE at 3 months of age was 21% lower in infants
who later became overweight67 than in those who remained normal weight, but this finding was not confirmed in larger subsequent studies.68,69 A longitudinal
study of 126 Pima Indians revealed that those in the
lowest REE tertile at baseline had the highest cumulative
incidence of a 10-kg weight gain 1 to 4 years later.70 In
contrast, the Baltimore Longitudinal Study did not find
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a relationship between initial REE and weight change
during a 10-year average follow-up of 775 men.71
Although weight gain always occurs when energy
intake exceeds energy expenditure, the amount of weight
that is gained after overfeeding may be genetically determined and certain individuals may be more resistant
to weight gain than others. Bouchard et al.72 found that
chronic overfeeding of 1000 kcal per day caused a variable increase in body weight among a group of 12
monozygotic twin pairs. However, the weight gained by
one twin was very similar to the weight gained by the
other. The differences in weight gained between twin
pairs may have been caused by differences in their thermogenic response to overfeeding. A recent study indicated that body fat gain in response to 8 weeks of
overfeeding was inversely related to changes in nonvolitional energy expenditure (e.g., fidgeting).73 Therefore,
nonvolitional energy expenditure during overfeeding
may be genetically determined and can prevent or limit
excessive weight gain in some individuals by considerable dissipation of excess ingested energy.
Diet-induced weight loss decreases REE, which contributes to weight regain. This phenomenon has led to
the “set-point theory,” which proposes that body weight
is predetermined so that weight loss (or weight gain) will
decrease (or increase) metabolic rate, to return body
weight to a preset value.74 Hypocaloric feeding in either
lean or obese persons causes a 15% to 30% decline in
REE, which cannot be explained completely by the concomitant decrease in body size or lean body mass and is
part of the normal metabolic adaptation to energy restriction.75 However, the decline in REE below predicted
values is a transient phenomenon that occurs during
negative energy balance but does not persist during
weight maintenance. Many studies have demonstrated
that long-term maintenance of lost weight does not cause
an abnormal decrease in REE or TEE when adjusted for
changes in body composition.76,77 A meta-analysis of 15
studies found that REE was similar in formerly obese and
never obese subjects.78 Therefore, the decline in absolute
REE and TEE that occurs after weight loss is likely to
contribute to recidivism; the decrease in energy metabolism appears to be largely appropriate for the changes in
body composition.
Adipose Tissue
Triglycerides present within adipose tissue are the
body’s major fuel reserve (Table 3). A lean adult has
about 35 billion adipocytes and each adipocyte contains
about 0.4 to 0.6 ␮g of triglyceride; an extremely obese
adult can have 4 times as many adipocytes (125 billion),
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Table 3. Endogenous Fuel Stores in a Man Weighing 70 kg
Mass
Tissue
Fuel source
Adipose tissue
Liver
Triglyceride
Glycogen
Proteina
Triglyceride
Proteina
Glycogen
Triglyceride
Glucose
Triglyceride
Free fatty acids
Muscle
Blood
aNot
g
13,000
100
300
50
6000
500
300
3
4
0.5
kcal
120,000
400
1200
450
24,000
2000
2700
12
35
5
normally considered a fuel source.
each containing twice as much lipid (0.8 to 1.2 ␮g of
triglyceride).79 The high energy density and hydrophobic
nature of triglycerides make it a 5-fold better fuel per
unit mass than glycogen. Triglycerides liberate 9.3
kcal/g when oxidized and are stored compactly as an oil
inside the fat cell, accounting for 85% of adipocyte
weight. By comparison, glycogen produces only 4.1
kcal/g when oxidized and is stored intracellularly as a gel
containing approximately 2 g of water for every gram of
glycogen. Therefore, adipose tissue represents an effective
mechanism for storing transportable fuel and permits
mobility and survival during periods of food deprivation.
In fact, the duration of survival during starvation depends on the amount of body fat mass. In lean men,
death occurs after approximately 2 months of starvation
when more than 35% (⬃25 kg) of body weight is lost.80
In contrast, obese persons have undergone therapeutic
fasts for more than a year without adverse consequences.
The longest reported fast was that of a 207-kg man who
ingested acaloric fluids, vitamins, and minerals for 382
days and lost 61% (126 kg) of his initial weight.81
The cornerstone of obesity therapy is to eat fewer
calories than are expended to consume endogenous fat
stores as fuel. Approximately 75% to 85% of weight that
is lost by dieting is composed of fat and 15% to 25% is
fat-free mass (FFM).82 Therefore, although an energy
deficit of approximately 3500 kcal is needed to oxidize 1
pound of adipose tissue, a 3500-kcal energy deficit will
cause more than a 1-pound loss in body weight because
of the oxidation of lean tissue and associated water losses.
In addition, there is regional heterogeneity in the distribution of fat loss, with greater relative losses of intraabdominal fat than total body fat mass, particularly in
men and women with increased initial intra-abdominal
fat mass.83,84 Most, if not all, of the loss of fat is caused
by a decrease in the size (lipid content) of existing fat
cells.85 There is also evidence in humans that large,
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long-term fat loss can decrease the number of fat cells.86
However, it is possible that the marked shrinkage caused
by severe weight loss may make some adipocytes visually
indiscernible by standard cell-counting techniques, leading to a false perception of decreased fat cell number.
Weight loss could eliminate fat cells by 2 possible mechanisms: dedifferentiation and apoptosis. Although adipocyte dedifferentiation, the morphological and biochemical reversion of mature adipocytes to preadipocytes, has
been identified in vitro, there is no evidence that this
process occurs in vivo.87 In contrast, adipoctye apoptosis
can be induced in vitro88 and has been shown to occur in
vivo in some patients with cancer.89 However, the possibility that adipocyte apoptosis is induced by weight
loss has not been studied.
Medical Complications of Obesity
Obesity is an important risk factor for many
serious medical complications (Table 4), which lead to
impaired quality of life, considerable morbidity, and
premature death. Many of the complications associated
with obesity have been reviewed previously.4,90,91 Gastrointestinal and other selected complications will be
discussed in this section.
Gastrointestinal Disease
Gastroesophageal reflux disease. Most,92–96 but
not all,97 large epidemiological studies have found that
gastroesophageal reflux disease (GERD) symptoms are
more common in obese than in lean persons. However, it
is unclear whether obesity actually causes reflux or is
simply associated with GERD. The relationship between
obesity and known factors that predispose to GERD,
such as resting lower esophageal sphincter (LES) pressure
and acidic lower esophageal pH, is unclear because of
conflicting results from different studies. Several studies
found no significant relationship between BMI and
GASTROENTEROLOGY Vol. 123, No. 3
esophageal acid reflux evaluated by 24-hour pH monitoring,98 –100 whereas one study, involving extremely
obese subjects, revealed that BMI correlated directly
with pathologic reflux, defined as an esophageal pH ⬍4
for more than 5% of the time.101
Although increased intra-abdominal pressure induced
by excessive abdominal girth may predispose obese persons to reflux, we are unaware of any randomized controlled trials that have evaluated whether weight loss
decreases reflux symptoms. In one study, conducted in
lean persons, diet-induced weight loss correlated directly
with improvement in reflux symptoms.102 However,
even modest weight loss of 2 to 3 kg caused a marked
improvement in symptom score, suggesting that changes
in diet rather than body weight may have been responsible for the beneficial clinical effects. In studies of
patients with class I103 and class III104 obesity who had
symptoms of GERD, diet-induced weight loss did not
improve symptoms or 24-hour esophageal pH values. In
contrast, the gastric bypass procedure consistently has
been shown to decrease GERD symptoms.105–107 In fact,
GERD symptoms often resolve immediately after surgery, before there is significant weight loss,101 suggesting that the elimination of acid or bile reflux, rather than
decreased weight, is responsible for the beneficial effect.
Although some studies have found that vertical-banded
gastroplasty (VBG) and gastric banding, which increase
resistance to flow through the proximal pouch, do not
alter LES pressure or increase episodes of reflux,108,109
severe gastroesophageal reflux can occur after VBG.110,111
Gallbladder disease. Obesity is an important
risk factor for gallbladder disease, particularly in women.
The risk of symptomatic gallstones increases linearly
with BMI (Figure 3).21,112 Data from the Nurses Health
Study demonstrated that, compared with lean women
(BMI ⬍24 kg/m2), obese women (BMI ⬎30 kg/m2) had
a 2-fold excess risk and extremely obese women (BMI
Table 4. Medical Complications Associated With Obesity
Gastrointestinal
Endocrine/metabolic
Cardiovascular
Respiratory
Musculoskeletal
Gynecologic
Genitourinary
Ophthalmologic
Neurologic
Cancer
Postoperative events
Gallstones, pancreatitis, abdominal hernia, NAFLD (steatosis, steatohepatitis, and cirrhosis), and possibly
GERD
Metabolic syndrome, insulin resistance, impaired glucose tolerance, type 2 diabetes mellitus, dyslipidemia,
polycystic ovary syndrome
Hypertension, coronary heart disease, congestive heart failure, dysrhythmias, pulmonary hypertension, ischemic
stroke, venous stasis, deep vein thrombosis, pulmonary embolus
Abnormal pulmonary function, obstructive sleep apnea, obesity hypoventilation syndrome
Osteoarthritis, gout, low back pain
Abnormal menses, infertility
Urinary stress incontinence
Cataracts
Idiopathic intracranial hypertension (pseudotumor cerebri)
Esophagus, colon, gallbladder, prostate, breast, uterus, cervix, kidney
Atelectasis, pneumonia, deep vein thrombosis, pulmonary embolus
September 2002
Figure 3. Relationship between the incidence of symptomatic gallstones (defined as cholecystectomy or newly diagnosed symptomatic
unremoved gallstones) and BMI in the Nurse’s Health Study. (Data
from Stampfer et al.112)
⬎45 kg/m2) had a 7-fold excess risk of symptomatic
gallstones.112 The annual incidence of symptomatic gallstones was 1% in women who had a BMI greater than 30
kg/m2 and 2% in those with a BMI greater than 45
kg/m2. The risk of obesity-related gallbladder disease is
smaller in men than in women. Data from 2 large
prospective studies of men,113,114 as well as the
NHANES III data from men and women, showed the
prevalence of gallstones was lower in men than in women
when both genders were matched on BMI. The relative
increase in risk with increasing BMI was also lower in
men.
The risk of gallstones increases during weight loss
because of increased bile cholesterol supersaturation, enhanced cholesterol crystal nucleation, and decreased gallbladder contractility.115 The incidence of new gallstones
is approximately 25% and 35% in obese patients who
experience rapid weight loss after treatment with a verylow-calorie (⬍600 kcal per day), low-fat (1 to 3 g per
day) diet116 –119 and gastric surgery,120 –123 respectively.
The risk of gallstone formation increases exponentially
when the rate of weight loss exceeds 1.5 kg (⬃1.5% of
body weight) per week.124 Dietary fat content also influences de novo gallstone formation during weight loss
induced by a very-low-calorie diet, presumably because
of the effect of ingested fat on gallbladder emptying;
ingesting a meal with 4 g of fat is a poor stimulus for
gallbladder emptying, whereas ingesting a meal with
10 g of fat causes maximal gallbladder contractility.125
Festi et al.126 found that increasing the fat content of a
very-low-calorie diet (⬍600 kcal per day) prevented the
development of new gallstones. The risk of developing
gallstones while dieting is much lower (0%–17%) in
patients who consume a low-calorie diet (⬎800 kcal per
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day) containing 15 to 30 g of fat per day than a verylow-calorie, low-fat diet.127–130 Moreover, increasing dietary fat content may not be as important for reducing
the risk of gallstones in low-calorie compared with verylow-calorie diet therapy.131 Ursodeoxycholic acid therapy
markedly decreases gallstone formation caused by either
a very-low-calorie diet119 or gastric surgery.121–122 A dose
of 600 mg per day provides maximal gallstone prevention and prophylactic therapy is cost-effective in patients
who are expected to achieve rapid weight loss.132
Pancreatitis. Although it seems logical that
obese patients should be at increased risk for gallstone
pancreatitis because of the increased prevalence of gallstones, few studies have evaluated this issue. However,
there is evidence from both retrospective and prospective
studies that obese patients who develop pancreatitis from
any cause experience a worse outcome than lean patients.
Most studies found that overweight and obese patients
are at higher risk for developing local complications and
severe pancreatitis.133–137 Several studies found that obesity also increased the risk of respiratory insufficiency134,136,138 and mortality.133 It has been hypothesized that increased fat deposited in the peripancreatic
and retroperitoneal spaces may predispose obese patients
to peripancreatic fat necrosis and subsequent local and
systemic complications.
Liver disease. Obesity is associated with a constellation of liver abnormalities, manifested by hepatomegaly, increased liver biochemistry values, and alterations in liver histology (macrovesicular steatosis,
steatohepatitis, fibrosis, and cirrhosis).139 Although these
abnormalities have been reported as individual entities
associated with obesity, they more likely represent a
spectrum of liver disease, now known as nonalcoholic
fatty liver disease (NAFLD).140 The exact prevalence of
different features of NAFLD in obese patients is not
known because of a paucity of data. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are the
most commonly elevated liver enzymes but they usually
do not exceed twice the upper limit of normal127; enzyme
levels often do not correlate with the severity of histological abnormalities.140 Dieting itself often causes a
transient increase in serum transaminase concentrations
and a decrease in serum alkaline phosphatase concentration during the first 6 weeks of active weight
loss.127,141,142 A retrospective analysis of liver biopsy
specimens obtained from overweight and obese patients
who had abnormal liver biochemistries but who did not
have overt findings of liver disease or evidence of acquired, autoimmune, or genetic liver disease, revealed
that 30% of patients had septal fibrosis and one-third of
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these (10% of the total group) had “silent” cirrhosis.143
In addition, many patients who have histological features
of NAFLD are obese. Composite data from a series of
studies found that 40% to 100% of patients with NASH
were obese.144 Data from autopsy studies, investigations
of obese patients undergoing obesity surgery, and crosssectional analyses of liver biopsy samples suggest that
steatosis occurs in ⬃75%, steatohepatitis in ⬃20%, and
cirrhosis in ⬃2% of obese patients.145–147
Although the clinical, laboratory, and histological features of NAFLD have been documented,138 –150 the
pathogenesis and natural history of this disease are not
well understood. Most patients with NAFLD are asymptomatic, but some may complain of fatigue, malaise, and
vague abdominal discomfort. Hepatomegaly has been
reported in up to 75% of patients with NAFLD. In
contrast to patients who have alcohol-induced steatohepatitis, the AST:ALT ratio is usually less than 1 in
patients who have NAFLD. In studies that observed
patients for 1 to 7 years, liver disease progressed in
approximately 40%, with cirrhosis occurring in approximately 10% of patients. Moreover, most patients with
simple steatosis had a benign clinical course, whereas
those with steatohepatitis, fibrosis, and cirrhosis were
more likely to develop clinical sequelae of severe liver
disease. Although only a small percentage of patients
with NAFLD eventually develop cirrhosis, the high
prevalence of obesity and obesity-related liver disease
makes NAFLD an important cause of cirrhosis in the
United States. Furthermore, obesity increases the risk of
fibrosis and cirrhosis in patients with alcoholic liver
disease151 and hepatitis C.152
The factors responsible for the development of
NAFLD in obese persons are not clear. There is increasing evidence that NAFLD is associated with abdominal
obesity (assessed by waist circumference), insulin resistance (defined by elevated fasting blood glucose and
insulin concentrations), diabetes, hypertriglyceridemia,
low serum high-density lipoprotein (HDL) cholesterol
concentrations, and hypertension.143,153–155 It has been
hypothesized that NAFLD is the result of 2 or more
insults to the liver.156 The first “hit” is steatosis, presumably caused by obesity-induced alterations in lipid
metabolism, including increased lipolysis of adipose tissue triglycerides, which increases free fatty acid delivery
to the liver, increased hepatic de novo lipogenesis, and
decreased hepatic fatty acid oxidation. The second “hit”
may be peroxidation of hepatic lipids and injury-related
cytokines, which can cause direct cellular injury, inflammation, and fibrosis.157
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Although weight loss typically is recommended for
obese patients with NAFLD, it is not known whether
this therapy changes the natural history of disease. A
gradual loss of 10% or more of body weight can correct
abnormal liver chemistries and decrease liver size, fat
content, and features of steatohepatitis.158 –160 However,
rapid weight loss after gastric surgery,146 very-low-calorie diets (VLCDs),161 or fasting162 decreases hepatic fat
content but can induce hepatic inflammation and exacerbate steatohepatitis.
Endocrinologic/Metabolic Disease
Metabolic syndrome. The metabolic syndrome,
also known as the insulin-resistance syndrome and syndrome X, represents a specific body phenotype in conjunction with a group of metabolic abnormalities that are
risk factors for CHD. Characteristics of this syndrome
include abdominal obesity, insulin-resistant glucose metabolism (hyperinsulinemia, impaired glucose tolerance,
impaired insulin-mediated glucose disposal, type 2 diabetes mellitus), dyslipidemia (hypertriglyceridemia, low
serum HDL-cholesterol concentration), and hypertension. Recently, additional metabolic abnormalities associated with abdominal obesity that are also risk factors
for CHD have been identified: increased serum concentrations of apolipoprotein B, small, dense low-densitylipoprotein (LDL) particles, and plasminogen activator
inhibitor 1 (PAI-1) with impaired fibrinolysis.163,164
Obesity itself is not a requirement for the metabolic
syndrome; metabolically obese, normal-weight persons,
presumably with increased abdominal fat mass, have
been identified.165
It has been hypothesized that insulin resistance is the
common pathogenic mechanism underlying the metabolic syndrome.166 However, factor analysis of nondiabetic participants in the Framingham Offspring Study
suggests that insulin resistance may not be the only
antecedent and that more than one independent physiological process is responsible for the observed cluster of
metabolic abnormalities.167 Although abdominal obesity
clearly is associated with insulin resistance, it is not clear
whether visceral (omental and mesenteric) fat or subcutaneous abdominal fat is more closely associated with
insulin resistance because of contradictory data from
different studies.168 –173 Moreover, the size of one depot
correlates closely with the size of the other,168 making it
difficult to separate the relationship of each one with
insulin sensitivity. In addition, it is not known whether
visceral or abdominal fat actually is involved in the
pathogenesis of the metabolic syndrome or whether these
are simply markers for persons who are at increased risk
for the metabolic complications of obesity.174
September 2002
Type 2 diabetes mellitus. It is likely that the
25% increase in the prevalence of diabetes in the last 20
years in the United States175 is caused by the marked
increase in the prevalence of obesity. BMI, abdominal fat
distribution, and weight gain are important risk factors
for type 2 diabetes mellitus. Data from NHANES III
found that two-thirds of adult men and women in the
United States diagnosed with type 2 diabetes have a BMI
of 27 kg/m2 or greater.91 Moreover, the risk of diabetes
increased linearly with BMI; diabetes prevalence was 2%,
8%, and 13% in those with BMI 25 to 29.9 kg/m2 (overweight), 30 to 34.9 kg/m2 (class I obesity), and ⱖ35 kg/m2
(class II/III obesity), respectively.175 Data from the Nurses
Health Study proved that the risk of diabetes begins to
increase in “normal” weight women when BMI exceeds
22 kg/m2.18,176 Increases in abdominal fat mass, waist
circumference, and waist-to-hip-circumference ratio all
increase the risk of diabetes at any BMI value.177–179
Weight gain during adulthood also increases the risk of
diabetes. For example, men and women 35 to 60 years of
age who gained 5 to 10 kg since age 18 to 20 years had
a 3-fold greater risk of diabetes than those who maintained their weight within 2 kg.18,19
Dyslipidemia. Obesity, particularly the abdominal obesity phenotype, is associated with hypertriglyceridemia, low HDL2 cholesterol, and an increased proportion of small, dense, LDL particles.180 –182 Most studies
also suggest that overweight and obesity are associated
with an increase in serum total and LDL-cholesterol
concentrations.183 However, BMI-associated differences
in total and LDL cholesterol are more pronounced at
lower body weights and become blunted with increasing
age. Data from NHANES III showed that the prevalence
of hypercholesterolemia (total blood cholesterol ⱖ240
mg/dL or 6.21 mmol/L) increased progressively with
increasing BMI in men, whereas the prevalence of hypercholesterolemia was highest at a BMI between 25
kg/m2 and 27 kg/m2 and did not increase further with
higher BMI values in women.183 The abnormalities in
serum lipids associated with obesity are clinically important and are clearly associated with an increased risk of
CHD.184,185
Cardiovascular Disease
CHD. Obese persons, particularly those with ab-
dominal fat distribution and those who gained weight
during young adulthood, are at increased risk for CHD.
The risk of CHD begins to increase at a “normal” BMI of
23 kg/m2 for men and 22 kg/m2 for women.186 The
presence of increased abdominal fat increases the risk of
CHD at any given BMI value. In fact, data from the
Nurses Health Study showed that women in the lowest
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BMI but highest waist-to-hip circumference ratio tertiles
had a greater risk of fatal and nonfatal myocardial infarctions than women in the highest BMI but lowest waistto-hip circumference ratio tertiles.187 A weight gain of 5
or more kg after 18 years of age also increases the risk of
fatal and nonfatal myocardial infarction.10,16 Most of the
increase in CHD is mediated by obesity-related increases
in risk factors, particularly hypertension, dyslipidemia,
impaired glucose tolerance/diabetes, and the metabolic
syndrome. It has been more difficult to show an independent effect of obesity on CHD in epidemiological
studies, possibly because of the long follow-up period
needed to detect CHD, the confounding effect of CHD
risk factors that affect body weight (such as cigarette
smoking), and the influence of body fat distribution.
Nonetheless, several long-term epidemiological studies
disclosed that overweight and obesity increased the risk
of CHD, even after correction for other known risk
factors.10,188 Therefore, the American Heart Association
recently added obesity to its list of major risk factors for
CHD189 and developed guidelines for achieving a healthy
body weight.190
Cerebrovascular and thromboembolic disease.
Overweight and obesity increase the risk of ischemic, but
not hemorrhagic, strokes in both men and women.191,192
The risk of fatal and nonfatal ischemic stroke increases
progressively with increasing BMI and is approximately
2-fold greater in obese than in lean persons. Obesity,
particularly abdominal obesity, also increases the risk of
venous stasis, deep vein thrombosis, and pulmonary embolism.193–195 Lower extremity venous disease may be a
consequence of increased intra-abdominal pressure, an
impaired fibrinolytic system, and increased inflammatory
mediators associated with abdominal obesity.196,197 Recent data obtained from California Medicare records revealed that elderly patients who underwent total hip
arthroplasty had a 2.5-fold increased risk of subsequent
hospitalization for symptomatic thromboembolic disease
(deep vein thrombosis or pulmonary embolism) if their
BMI was 25 kg/m2 or greater.198
Hypertension. Several large epidemiological studies
have documented the linear relationship between hypertension and BMI.188,199 –201 Data from NHANES III
demonstrated that the age-adjusted prevalence of hypertension (defined as systolic blood pressure ⱖ140 mm
Hg, diastolic blood pressure ⱖ90 mm Hg, or use of
antihypertensive medications) was more than 2-fold
higher in obese men and women (42% and 38% prevalence rates, respectively) than in lean men and women
(⬃15% prevalence rate in both men and women).183
Abdominal fat distribution is an independent risk factor
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for hypertension and in some studies was a better predictor of hypertension than BMI.202–204 Weight gain also
increases hypertensive risk. Longitudinal assessment of
participants in the Framingham Study found that blood
pressure increased by 6.5 mm Hg for every 10% increase
in body weight.200
Pulmonary Disease
Pulmonary Function
Obesity is associated with pulmonary function
abnormalities, obesity-hypoventilation syndrome, and
obstructive sleep apnea.205 However, no epidemiological
or longitudinal studies have systematically evaluated the
prevalence or natural history of pulmonary disease in
obese persons. Obesity, particularly when there is excess
abdominal fat, can interfere mechanically with lung
function. Increased weight on the chest wall and thoracic
cage decreases respiratory compliance, increases the work
of breathing, restricts ventilation (measured as decreased
total lung capacity, forced vital capacity, and maximal
ventilatory ventilation), and limits ventilation of lung
bases with subsequent atelectasis, ventilatory-perfusion
mismatching, and increases in alveolar-to-arterial gradient.
Obesity-hypoventilation. Patients with obesityhypoventilation syndrome have a PCO2 ⬎50 mm Hg
because of decreased ventilatory responsiveness to hypercapnea and/or hypoxia and an inability of respiratory
muscles to meet the increased ventilatory demand caused
by the mechanical effects of obesity. Alveolar ventilation
is reduced because of shallow and inefficient breathing
related to decreased tidal volume, inadequate inspiratory
strength, and an elevated diaphragm. Patients may become more symptomatic when lying down because
abdominal pressure pushes up the diaphragm, which
increases intrathoracic pressure, causing further compromise in lung function and respiratory capacity. A severe
form of the obesity-hypoventilation syndrome, known as
the Pickwickian Syndrome after an obese character in
Charles Dickens’ Pickwick Papers, is associated with extreme obesity, irregular breathing, somnolence, cyanosis,
secondary polycythemia, and right ventricular dysfunction.
Obstructive sleep apnea. Obstructive sleep apnea
syndrome is characterized by excessive episodes of apnea
and hypopnea during sleep caused by partial or complete
upper airway obstruction, despite persistent respiratory
efforts. The interruption in nighttime sleep and arterial
hypoxemia cause daytime sleepiness and cardiopulmonary dysfunction. Most patients with sleep apnea have a
BMI ⬎30 kg/m2, abdominal fat distribution, and a large
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neck girth (ⱖ17 inches in men and ⱖ16 inches in
women).206 –210 In addition, midlife waist circumference
and an increase in waist circumference over 30 years of
adult life are independent risk factors for sleep apnea in
old age (75 to 91 years of age).211 However, the presence
of sleep apnea in lean persons demonstrates that other
factors, such as cephalometric defects that are independent of body weight and regional fat distribution, also
contribute to risk.212
Musculoskeletal Disease
Gout. Both cross-sectional and longitudinal studies have demonstrated that obesity is associated with
hyperuricemia and gout.213–214 Moreover, hyperuricemia
is associated with abdominal obesity and the metabolic
syndrome,215–216 and insulin resistance decreases renal
uric acid clearance.217
Osteoarthritis. Overweight and obesity increase
the risk of osteoarthritis of weight-bearing joints, particularly the knees, presumably because body weight
exerted across the knee is much greater than that exerted
across the hips during weight-bearing activities.218 –219
The relationship between body size and osteoarthritis is
stronger in women than in men and even small increases
in body weight can cause osteoarthritis in women. A
study of twin pairs found that individuals who had
symptomatic or asymptomatic lower extremity osteoarthritis were 3 to 5 kg heavier than their paired siblings.220
Data from longitudinal studies suggest that obesity is
involved in the pathogenesis of osteoarthritis because
obesity can precede osteoarthritis by decades.220 –221
Some studies also have found that obesity is associated
with osteoarthritis of the hand, suggesting that increased
load across a joint may not be the only pathogenic
mechanism responsible for joint disease.222–223
Cancer
Overweight and obesity are associated with an
increased risk of esophageal, gallbladder, pancreatic, breast,
renal, uteral, cervical, and prostate cancer.92,224 –226 A direct
relationship between BMI and colon cancer has been
observed for both men and women in most,226 –228 but
not all,229,230 epidemiological studies. The effect of BMI
is strongest for distal cancers and in those with a family
history of colorectal cancer.231 Obesity and weight gain
after the age of 18 years increase the risk of breast and
endometrial cancer mortality.226,232 However, the greater
risk of breast cancer with increasing BMI is limited to
postmenopausal women, and increased BMI actually may
be protective of breast cancer in premenopausal women.233
Moreover, it is difficult to determine how much of the
September 2002
association between obesity and cancer is attributable to
obesity per se or to a high-fat, high-calorie diet because
both factors often are correlated.
Reproductive and Urinary Tract
Abnormalities in Women
Obesity is associated with irregular menses, amenorrhea, and infertility.234 Obesity during pregnancy
increases the risk for gestational diabetes and hypertension,235 a complicated delivery,236 and congenital malformations.237 Obesity is an independent risk factor for
urinary incontinence, even when the data are adjusted for
age and parity.238 –240 In one study, the odds ratio for
daily incontinence increased by 1.6 for every 5-unit
increase in BMI.240 Presumably, increased intra-abdominal pressure is an important etiologic factor for incontinence, and incontinence usually resolves in extremely
obese patients after massive weight loss.241
Neurological Disease
Idiopathic intracranial hypertension (IIH), also
known as pseudotumor cerebri, is a syndrome of increased
intracranial pressure in the absence of hyrocephalus or a
space-occupying lesion. This syndrome often causes
symptoms of headache, vision abnormalities, tinnitus,
and sixth nerve paresis. Increased BMI is associated with
an increased prevalence of IIH, and even persons who are
as little as 10% above ideal body weight are at increased
risk.242,243 The notion of a causal relationship between
obesity and IIH is supported by the observation that
marked weight loss in extremely obese patients with IIH
decreases intracranial pressure and resolves most associated clinical signs and symptoms.244,245 Even modest
weight losses of ⬃6% of body weight have been associated with resolution of papilledema.246
Ophthalmological Disease
Several epidemiological studies have shown that
overweight and obesity are associated with an increased
prevalence of cataracts and cataract surgery.247–250 Moreover, excess abdominal fat distribution, assessed by
waist-to-hip-circumference ratio, is an additional risk
factor.250,251 It is not known whether obesity causes or is
simply associated with premature cataracts. However,
several obesity-related abnormalities, such as insulin resistance, elevated serum uric acid concentrations, and an
increase in inflammatory mediators, may contribute to
cataract formation.
Psychological Abnormalities
Approximately 20% to 30% of obese patients
who seek weight reduction at university clinics suffer
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from depression or other psychological disturbances.252
However, there is only limited evidence of increased
psychiatric or emotional abnormalities in obese compared with normal-weight subjects when both are recruited from the general population.253 Obese women
may be at greater risk of psychological abnormalities
than obese men, presumably because of the greater social
pressure on females to be thin.254
Some behavioral abnormalities may contribute to obesity. Binge eating is defined as eating a large amount of
food in a short period of time, accompanied by feelings of
loss of control and guilt. The diagnosis of binge-eating
disorder is made when these episodes occur at least twice
a week for 6 or more months and overeating is not
accompanied by compensatory purging behavior to curb
weight gain.255,256 Approximately 10% to 15% of obese
persons who seek weight reduction have binge-eating
disorder compared with only 2% in the general population.257 Patients with this disorder who enroll in weight
loss programs typically are more obese and may be more
refractory to weight loss than those who do not have the
disorder. Pharmacological or behavioral treatment of
binge eating can decrease binging episodes but, paradoxically, often do not induce weight loss.258 A second
eating disorder, known as the night-eating syndrome, also is
linked to obesity, but occurs less frequently than bingeeating disorder.259 Affected patients consume more than
50% of their daily intake after dinner, have delayed sleep
onset, report multiple awakenings at night that often are
accompanied by eating, and experience morning anorexia.
Quality of Life and Function
Obesity has been associated with impaired quality
of life. One study found that obese persons who sought
treatment at an outpatient university-based weight management center had profound abnormalities in healthrelated quality of life, measured by the Medical Outcomes Study Short-Form Health Survey (SF-36).260
Obesity was associated with negative effects on all 8
domains assessed by the SF-36, particularly bodily pain,
which measures the severity of pain and the impact of
pain on normal function. On all SF-36 domains, higher
BMI values were associated with greater adverse effects.
Patients with class III obesity exhibited particularly poor
scores in physical function, general health perception,
vitality, and bodily pain.
Obesity also is associated with impairment in productivity in the workplace, manifested by increased sick
leave absences and disability claims.261,262 The effect of
obesity on workplace function has considerable economic
impact. For example, it was estimated that paid sick
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leave and disability insurance cost U.S. businesses more
than $3 billion in 1994.261
Benefits of Intentional Weight Loss
Effect on Mortality
There is no conclusive evidence that weight loss
decreases mortality in obese persons. In fact, most epidemiological studies have found that weight loss or
weight fluctuation was associated with increased mortality.263 However, these studies did not distinguish between intentional and unintentional weight loss, which
may have confounded the results because unintentional
weight loss often is caused by preexisting illness. Three
studies have reported the effect of intentional weight loss
on survival.264 –266 Each study reported on a different
subgroup within the American Cancer Society’s Cancer
Prevention Study I, which obtained baseline data between 1959 and 1960 in mostly white men and women
and followed the participants for an average of 12 years.
The first study was performed in overweight and obese
women.264 In women with obesity-related illnesses, any
amount of intentional weight loss was associated with a
20% reduction in all-cause mortality, primarily caused
by a decrease in mortality from obesity-related cancers
and diabetes. In women who did not have a preexisting
illness, there was no overall relationship between intentional weight loss and mortality. However, a loss of ⱖ20
pounds in the preceding year was associated with a 25%
reduction in all-cause, cardiovascular, and cancer mortality, whereas a loss of ⬍20 pounds that occurred more
than 1 year before the initiation of the study was associated with a small increase in mortality. The second
study evaluated overweight and obese men.265 In men
with obesity-related illnesses, intentional weight loss did
not affect total or cardiovascular mortality, but mortality
from cancer was increased in those who had lost ⱖ20
pounds. In men who did not have a preexisting illness,
intentional weight loss was not associated with total,
cardiovascular, or cancer mortality, but diabetes-associated mortality was increased in those who lost ⱖ20
pounds. The third study evaluated overweight and obese
men and women who had diabetes.266 Intentional weight
loss was associated with a 25% reduction in total mortality and a 28% reduction in cardiovascular disease and
diabetes-related mortality. In aggregate, these studies
suggest that intentional (possibly transient) weight loss
may improve survival in overweight and obese persons
who have an obesity-related illness, particularly type 2
diabetes mellitus. However, these data must be interpreted with caution because weight loss was self-reported
and may have occurred at any time before the initial
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visit. In addition, possible changes in weight that may
have occurred in the subsequent 12-year follow-up period were not determined. Moreover, intentional decreases in weight before 1960 may not have the same
effect on mortality as intentional decreases in weight
today because of improvements in medical care.
Effect on Morbidity
Intentional weight loss improves many of the
medical complications associated with obesity.4,267 Moreover, many of these beneficial effects are apparent after
only modest weight losses of 5% to 10% of initial body
weight.268 There is also evidence that weight loss can
delay or decrease the risk of developing new obesityrelated diseases, such as diabetes.269,270
Cardiovascular disease. Obese persons who develop CHD often have more than one metabolic risk
factor for CHD. The hazard of developing CHD is related directly to the concomitant burden of risk factors.
Although effective pharmacological approaches are available to treat individual risk factors, modest weight loss
can affect the entire cluster of risk factors simultaneously.
Data from the Framingham Offspring Study indicate
that a weight loss of 5 pounds (2.25 kg) or more over 16
years was associated with a 48% and 40% decrease in the
sum of risk factors (highest quintile of systolic blood
pressure, serum triglyceride, serum total cholesterol,
fasting blood glucose, and BMI and lowest quintile of
HDL-cholesterol) in men and women, respectively.271
Weight loss also improves cardiovascular structure
and function. Weight loss decreases blood volume and
hemodynamic demands on the heart, left ventricular
mass and chamber size, and septal wall thickness.272–275
These improvements in cardiac function may be responsible for the decrease in symptoms of chest pain and
dyspnea reported in patients who lost 23% (28 kg) of
their body weight after gastric surgery for obesity.276
Furthermore, weight loss may decrease the progression of
atherosclerosis. B-mode ultrasound assessment of the carotid artery, a surrogate measure of coronary atherosclerosis, was performed at baseline and 4 years later in 3
groups of subjects: (1) obese persons who underwent
gastric surgery for obesity and lost 19% of their body
weight, (2) obese persons who were not treated and
maintained their body weight, and (3) lean volunteers.277
The progression rate of intimal wall thickness was similar in both obese subjects who lost weight and lean
volunteers, but was 3 times higher in the obese patients
who maintained their body weight.
Type 2 diabetes mellitus. Both negative energy
balance and weight loss improve insulin sensitivity and
glycemic control in obese patients with type 2 diabetes
September 2002
mellitus. In one study, as little as a 5% weight loss at the
end of 1 year decreased fasting blood glucose, insulin,
and hemoglobin A1c concentrations and medication requirements in obese, diabetic patients who were being
treated with oral hypoglycemic agents.278 The need for
hypoglycemic medication was decreased in all subjects
who lost 15% or more of their body weight. An average
weight loss of ⬃30% of initial body weight in patients
with class III obesity who had gastric bypass surgery
resulted in marked long-term improvements in glucose
homeostasis; 83% of patients with type 2 diabetes and
99% of patients with impaired glucose tolerance
achieved normal fasting blood glucose, insulin, and
glycosylated hemoglobin concentrations.279 However,
weight loss does not improve glycemic control in all
obese patients who have diabetes280 and it is possible that
patients with long-term disease and more severe pancreatic failure are resistant to the benefits of weight loss.
Sustained weight loss is effective in preventing the
development of new cases of diabetes in obese persons.270,281–282 Data from the Framingham Study revealed that the risk of diabetes decreased by 33% in those
who lost 3.7 to 6.8 kg and by 51% in those who lost
more than 6.8 kg during 16 years of observation.270 Data
from the Finnish Diabetes Prevention Study and the
United States Diabetes Prevention Program Study demonstrate that changes in lifestyle that result in modest
(⬃5%) weight loss decreased the 4- to 6-year cumulative
incidence of diabetes by 58% in overweight and obese
men and women with impaired glucose tolerance.283,283a
A 16% weight loss after gastric surgery in severely obese
patients (initial BMI ⫽ 41 kg/m2 participating in the
Swedish Obese Subjects (SOS) study was associated with
a 5-fold decrease in the risk of diabetes over an 8-year
period (diabetes incidence of 18.5% in the control group
and 3.6% in the surgery-treated group).282
Achieving weight loss is particularly difficult in patients with type 2 diabetes. Several studies have shown
that obese patients with type 2 diabetes lose less weight
than obese patients without diabetes.284 –286 Moreover,
weight loss success may be inversely related to duration
and severity of diabetes. In one study, obese patients with
a more severe stage of disease (defined as those controlled
by hypoglycemic agents) were more refractory to weight
loss than those with a milder form of disease (defined as
those controlled by diet therapy alone).286 The reasons for
the blunted weight loss response in patients with diabetes is not known but might be related to energy-conserving effects (e.g., reduced glycosuria) and tendency
toward weight gain associated with pharmacological diabetes therapy.287
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Dyslipidemia. Most studies have found that
weight loss decreases serum triglyceride, total cholesterol, and LDL-cholesterol concentrations and increases
serum HDL-cholesterol concentration.4,288 However, the
time course of lipid changes is influenced by the state of
energy balance and other dietary and physical factors.
The greatest improvements in serum triglyceride, total
cholesterol, and LDL-cholesterol concentrations tend to
occur in the first 4 to 8 weeks of weight loss.289,290
During the period of active weight loss serum HDLcholesterol concentration also decreases, but later increases once weight loss stabilizes.288 In addition, dietinduced weight loss in conjunction with exercise has a
greater beneficial effect on LDL-cholesterol than either
treatment alone.291 The beneficial effect of weight loss on
serum lipids is greater in men than in women,288 but this
probably is caused by differences in baseline BMI and
serum lipid levels than gender per se.292 Adjustment for
body size and initial lipid profile eliminates many of the
putative gender differences.
In general, the degree of improvement in serum lipids
is related to the amount of weight lost, and weight
regain will lead to relapse in triglyceride and cholesterol
concentrations. At 2 years, a sustained weight loss of 5%
is sufficient to maintain the reduction in serum triglyceride concentrations, whereas serum total and LDL
cholesterol revert toward baseline if at least a 10%
weight loss is not maintained.289,290,293,294 Of the lipid
subfractions, HDL cholesterol is the most resistant to
change; nonpharmacologic increases in HDL may require
a large amount of weight loss, a period of weight stabilization, and concomitant exercise training.
Hypertension. Weight loss, independent of sodium restriction, decreases systolic and diastolic blood
pressure.295 One of the largest intervention studies, the
Trials of Hypertension Prevention Phase II (TOHP II),
randomized approximately 1200 overweight and obese
participants to a dietary weight loss intervention or usual
care.296 The results demonstrated a dose-response relationship between weight loss and blood pressure at 36
months; an average weight loss of 8.8 kg in the highest
weight loss quintile was associated with a reduction of 7
mm Hg systolic and 5 mm Hg diastolic blood pressure,
a loss of 2.6 kg was associated with a reduction of 4.5
mm Hg systolic and 2.5 mm Hg diastolic blood pressure, and a loss of 0.1 kg was associated with a reduction
of 2.0 mm Hg systolic without a change in diastolic
blood pressure. Participants who lost a considerable
amount of weight in the first 6 months and then regained
most or all of their lost weight had a marked decline in
blood pressure at 6 months, followed by a steady increase
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to near baseline values by the end of the study. In
extremely obese patients who already have hypertension,
marked weight loss induced by gastric surgery improves
or completely resolves hypertension in approximately
two-thirds of patients.297,298 Recent data from the SOS
study question the duration of the effect of weight loss on
blood pressure. The beneficial effect of weight loss on
blood pressure observed at 1 and 2 years after gastric
surgery disappeared by 3 years, and both systolic and
diastolic blood pressure continued to increase gradually
for the next 5 years.282 The reason for the discrepancy
between studies is not clear but may be related to the
larger weight gain from nadir weight in the surgically
treated group (⬃11 kg) than in the highest weight loss
quintile of the diet-treated group (⬃1 kg) although
surgical therapy resulted in greater overall weight loss
(16% of initial weight) than did successful diet therapy
(⬃10% of initial weight). These data suggest that current energy balance and the direction of weight change
are also important factors in controlling blood pressure.
The ability of weight loss to prevent the future development of hypertension has also become controversial
because of the SOS report. Several large prospective
epidemiological and intervention studies found that
weight loss decreased the incidence of hypertension. The
risk of new cases of hypertension in normotensive women
who were followed for 12 to 15 years in the Nurses
Health Study correlated directly with changes in body
weight; weight losses of 5.0 to 9.9 kg and 10 or more kg
were associated with a 15% and 26% decreased risk of
hypertension, respectively.20 In TOHP II, persons who
maintained a weight loss of at least 4.5 kg at 36 months
had a 65% decrease in the risk of hypertension compared
with the control group who gained 1.8 kg.296 In contrast,
the beneficial effect of weight loss on the risk of hypertension at 2 years after gastric surgery in the SOS
study269 disappeared by 3 years; the risk was still the
same as that for the control group through 8 years of
observation, despite persistent weight loss.282 Surprisingly, the SOS study found a striking differential effect
of weight loss on the incidence of obesity-related diseases. Despite the disappointing effect on hypertension,
long-term surgically induced weight loss caused a
marked and persistent reduction in the risk of diabetes.
Respiratory disease. Pulmonary function, obstructive sleep apnea, and obesity hypoventilation improve with weight loss. Marked weight loss of ⬃30%
body weight in patients with class III obesity decreases
the severity of sleep apnea and often results in complete
resolution of obstructive sleep apnea syndrome when the
respiratory disturbance index, defined as the average
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number of apnea or hypopnea episodes per hour of sleep,
is ⱕ40.299 –301 However, even modest weight loss of
⬃10% body weight decreases the respiratory disturbance
index, improves sleep patterns, and decreases daytime
hypersomnolence.302 The weight loss–induced decrease
in upper airway collapsibility may be responsible for the
decrease in apnea severity, so initial critical upper airway
collapsibility pressure may determine how much weight
loss is needed to achieve a beneficial effect.303 Surgically
induced weight loss has been shown to improve and
resolve obesity hypoventilation syndrome, with correction of resting room air arterial blood gases, lung volumes, and cardiac filling pressures.301,304 Improvements
in sleep apnea and obesity hypoventilation are maintained with persistent weight loss, but relapse occurs in
those who regain lost weight. It is not known whether
there is a critical threshold of weight loss, whether this
threshold differs among patients, and which patients are
likely to achieve benefits in respiratory status from
weight loss.
Reproductive and urinary tract function in
women. Weight loss after gastric bypass surgery has
been shown to correct urinary overflow incontinence and
eliminate the need for perineal pads.241 Marked weight
loss improves fertility and patients who were previously
amenorrheic and infertile begin to ovulate and can become pregnant after bariatric surgery. Therefore, sexually
active women should take contraceptive precautions after
weight loss if pregnancy is not desired.
Quality of life and function. Data from several
studies suggest that weight loss improves physical function and health-related quality of life. The precise
amount of weight loss needed to alleviate symptoms or
prevent osteoarthritis in obese persons is not known.
However, the magnitude of weight that is lost is directly
correlated with improvement in symptoms, increase in
pain-free range of motion, and decrease in analgesic use
in the obese patient with osteoarthritis.305 Most patients
with class III obesity experience relief of pain in one or
more joints after marked weight loss induced by obesity
surgery.306 In subjects with class I obesity, an average
weight loss of 8.6 kg after 13 weeks of treatment with a
reduced-calorie diet, physical activity, and behavior therapy was associated with marked improvements in healthrelated quality of life, measured by the physical function,
general health perception, vitality, and mental health
domains of the SF-36.307 Data obtained at 2 years in the
SOS study found that weight loss, induced by gastric
surgery, improved health-related quality of life as measured by instruments that evaluated social interaction,
anxiety and depression, mood, perceived health, and
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daily activities, whereas no changes in these variables
were noted in the control group.308 The improvements in
health-related quality of life parameters were directly
correlated with the amount of weight lost. In addition, in
years 2, 3, and 4 of the SOS study, the number of sick
days and disability pension days awarded for short-term
and long-term illness or disability was lower in those
who lost ⬃20% to 25% of initial body weight after
gastric surgery than in the control group, particularly in
subjects who were older than 46 years of age.309
Medical Therapy
At any given time, approximately 45% of women
and 30% of men in the United States are actively trying
to lose weight.310 Although many obese persons can lose
weight by dieting, successful long-term weight management is much more difficult. Weight loss and subsequent regain is known as “weight cycling” or “yo-yo
dieting” and may have adverse psychological311 and medical312 consequences. However, as noted previously, most
observations of adverse medical outcomes associated with
weight cycling fail to distinguish intentional from unintentional weight loss and include both lean and obese
persons. The National Task Force on the Prevention and
Treatment of Obesity concluded that the available data
regarding effects of weight cycling on health are inconclusive and should not prevent obese persons from trying
to lose weight.313 Additional research is still needed to
determine whether unsuccessful dieting can cause net
harm.
The current therapeutic tools that are available for
weight management include dietary intervention, physical activity, behavior modification, pharmacotherapy,
surgery, and intragastric balloons (not available in the
United States).
Dietary Intervention
Dietary intervention is the cornerstone of weight
loss therapy because it is easier for most obese persons to
achieve negative energy balance by decreasing food intake than by increasing physical activity. Most diets
proposed for losing weight vary in 2 principal dimensions– energy content and macronutrient composition.
However, the energy content, and not the relative macronutrient composition of the diet, is the primary determinant of weight loss.
Energy content. VLCDs provide ⬍800 kcal per
day and usually contain small amounts of fat (ⱕ15 g per
day) and large amounts of protein (70 to 100 g per day).
These diets may be consumed as commercially prepared
liquid formulas, with or without nutritional bars, or as
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897
regular foods consisting of mostly lean meat, fish, or fowl
(the latter known as a protein-sparing modified fast).
Low-calorie diets (LCDs) contain 800 to 1500 kcal per
day, which can be provided as liquid formula, nutritional
bars, regular food, or some combination of these. A
balanced-deficit diet (BDD) usually provides ⱖ1500 kcal
per day of conventional foods, with an appropriate balance of macronutrients.
Obesity treatment guidelines issued by the NIH4
recommend that persons who are overweight (BMI of
25.0 to 29.9 kg/m2) and who have 2 or more risk factors
should decrease their energy intake by approximately
500 kcal per day. This energy deficit, which is also
recommended for persons with class I obesity (BMI of 30
to 34.9 kg/m2), will result in approximately a 1-pound
(0.45 kg) weight loss per week and about a 10% reduction of initial weight at 6 months. Persons with class II
(BMI of 35.0 to 39.9 kg/m2) or III (BMI ⱖ40 kg/m2)
obesity should aim for a more aggressive energy deficit of
500 to 1000 kcal per day, which will produce approximately a 1- to 2-pound weight loss per week and approximately a 10% weight loss at 6 months.
To prescribe a diet that induces a specific energy
deficit, it is necessary to know the patient’s daily energy
requirements. Although REE and TEE can be measured,
the technology needed to make these measurements is
expensive and not readily available to most clinicians.
Total daily energy requirements can be estimated by
using standard equations based on the patient’s size, age,
gender, and activity level, such as the Harris-Benedict314
or the World Health Organization equations (Table
5).315 However, the use of standard equations is cumbersome and may be unreliable in obese persons because
these equations can underestimate or overestimate energy
expenditure significantly. We suggest using the simple
Table 5. Commonly Used Formulas for Calculating Resting
Energy Expenditure
Harris-Benedict Equations314
Men ⫽ 66 ⫹ (13.7 ⫻ W) ⫹ (5 ⫻ H) ⫺ (6.8 ⫻ A)
Women ⫽ 665 ⫹ (9.6 ⫻ W) ⫹ (1.8 ⫻ H) ⫺ (4.7 ⫻ A)
World Health Organization Equations315
Age (yrs)
0–3
3–10
10–18
18–30
30–60
⬎60
Male
(60.9
(22.7
(17.5
(15.3
(11.2
(13.5
⫻
⫻
⫻
⫻
⫻
⫻
W)
W)
W)
W)
W)
W)
⫺
⫺
⫹
⫹
⫹
⫹
54
495
651
679
879
987
Female
(61.0 ⫻ W) ⫺ 51
(22.5 ⫻ W) ⫹ 499
(12.2 ⫻ W) ⫹ 746
(14.7 ⫻ W) ⫹ 996
(8.7 ⫻ W) ⫹ 829
(10.5 ⫻ W) ⫹ 596
W, weight in kg; H, height in cm; A, age in years.
An adjusted body weight rather than actual body weight should be
used for obese patients. Adjusted body weight ⫽ ideal body weight ⫹
[(actual body weight ⫺ ideal body weight) ⫻ (0.25)].
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Table 6. Suggested Energy and Macronutrient Composition
of Initial Reduced-Calorie Diet
Body weight (pounds)
Suggested energy intake (kcal/d)
150–199
200–249
250–299
300–349
ⱖ350
1000
1200
1500
1800
2000
Macronutrient composition:
Total fat
Saturated fatty acids
Monosaturated fatty acids
Polyunsaturated fatty acids
Cholesterol
Protein
Carbohydrate
20%–30% of total calories
8%–10% of total calories
Up to 15% of total calories
Up to 10% of total calories
⬍300 mg/day
15%–20% of total calories
55%–65% of total calories
dietary guidelines outlined in Table 6. Although patients who follow these guidelines usually will lose
weight, some may not fully comply with their prescribed
diets. Therefore, dietary energy content must be adjusted
regularly, based on a trial-and-error approach.
The effectiveness of LCDs has been evaluated in more
than 30 prospective randomized clinical trials, which
demonstrated that a 1000 to 1500 kcal per day LCD
produces about an 8% loss of body weight after 16 to 26
weeks of treatment.4 In these studies, diets were prescribed to provide a predetermined calorie target rather
than as an estimated energy deficit for each subject. The
results from these studies may differ from those obtained
by simply prescribing an LCD in clinical practice because
the participants in these trials volunteered for a weight
loss study and most received some form of behavior
modification therapy as part of the study protocol.
Although the use of VLCDs usually produces a loss of
about 15%–20% of initial weight in 12 to 16 weeks of
treatment, this approach is associated with poor maintenance of weight loss.294,316 –320 In several randomized
trials,294,316 –320 weight regain was greater after VLCD
than after LCD therapy, so that weight loss 1 year after
treatment was not different between the 2 diets. Moreover, initial weight loss with a VLCD is similar to that
obtained with an LCD when the diets are served in the
same manner. Weight loss in patients given a liquid diet
containing 420 kcal per day was not significantly greater
than that in persons who consumed a liquid diet containing 800 kcal per day,321,322 suggesting that patients
treated with VLCDs are either less compliant with their
diet or experience a greater decline in energy expenditure
than those treated with an LCD. In addition, the use of
VLCDs increases the risk of dieting-associated medical
complications, such as hypokalemia, dehydration, and
gallstone formation. Therefore, patients treated with a
GASTROENTEROLOGY Vol. 123, No. 3
VLCD require closer medical monitoring than those
treated with an LCD.
Meal replacements. The use of portion-controlled
servings can enhance weight loss because obese persons
who consume a diet of self-selected table foods tend to
underestimate their energy intake. For example, one
study found that obese persons who claimed they were
unable to lose weight on an LCD actually consumed
twice as many calories as they recorded in daily food
records.66 Underestimation is likely to result from underestimating serving sizes or failing to identify hidden
calories from fat and sugar. Providing prepackaged prepared meals can enhance long-term compliance. In a
randomized controlled trial conducted in persons with
hypertension, dyslipidemia, or diabetes, those who received prepackaged prepared meals lost 3 times as much
weight (⬃6 kg) at the end of 1 year as those randomized
to a standard exchange system diet (⬃2 kg).323 Jeffery et
al.324 found that obese subjects who were prescribed a
self-selected LCD of 1000 kcal per day lost less weight
than those who were prescribed the same number of
calories but were given their breakfast and dinner meals.
In a follow-up study, these investigators showed that the
provision of a structured meal plan, rather than providing patients the foods per se, was responsible for the
success of the portion-controlled diet.325 Subjects who
were provided a meal plan that told them precisely what
foods to purchase lost more weight than those who were
prescribed the same number of calories but consumed a
self-selected diet. Providing foods, in addition to the
meal plan, did not produce greater weight loss than the
meal plan alone.
The use of liquid formula meal replacements can be
effective for long-term weight management. In a randomized controlled trial conducted in Germany, subjects
who replaced 2 meals a day with a liquid formula (SlimFast; SlimFast Foods Co., West Palm Beach, FL) lost 8%
of initial weight during the first 3 months compared
with a loss of only 1.5% in those randomized to receive
the same number of calories as a self-selected diet.326
More importantly, those who continued to use the supplement to replace one meal and one snack a day maintained a weight loss of 11% at 27 months and of 8% at
51 months.327 The long-term effectiveness of a liquidformula meal replacement also has been demonstrated in
a large uncontrolled trial performed in the United
States.328
Macronutrient composition. Macronutrient composition does not affect weight loss unless it influences
total energy intake. Traditionally, low-fat diets are prescribed to help obese patients lose weight because these
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diets facilitate energy restriction. Dietary fat is composed
primarily of triglycerides, which increase food palatability and energy density. Data from epidemiological and
diet intervention studies suggest that increasing dietary
fat increases total energy consumption and body
weight.329 In addition, the results from a large number of
studies support the notion that decreasing fat intake,
while allowing ad libitum intake of carbohydrate and
protein, leads to a spontaneous decrease in total energy
intake and weight loss. A meta-analysis of 37 intervention studies that prescribed a Step I or Step II low-fat
(ⱕ30% kcal as fat) diet recommended by the National
Cholesterol Education Program to decrease the risk of
cardiovascular disease found a direct relationship between changes in dietary fat and body weight (Figure
4).330 Another meta-analysis of 19 studies showed that
weight loss produced by a low-fat ad libitum diet was
directly related to the severity of obesity; subjects who
were more obese lost greater amounts of weight on this
diet than those who were less obese.331
Diets that focus on reducing fat intake alone produce
less initial weight loss than those that restrict both fat
and total energy intake. Schlundt et al.332 found that
obese subjects who were instructed to eat 25 g/day of fat,
with ad libitum intake of carbohydrate, lost 4.6 kg in 20
weeks, while those who were prescribed the same fat goal
as part of a 1200 to 1500 kcal per day diet lost 8.8 kg.
However, it is not clear which dietary approach is superior for long-term weight maintenance because of conflicting data showing worse,332 the same,333 or better334
weight loss at 1 and 2 years with a low-fat ad libitum
Figure 4. Relationship between changes in dietary fat intake and
body weight from selected dietary intervention studies that were
designed to improve plasma lipids by following the National Cholesterol Education Program’s Step I and Step II diets. (Reprinted with
permission from Yu-Poth et al.330 © Am J Clin Nutr. American Society
for Clinical Nutrition.)
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diet than with an LCD. Data from the National Weight
Control Registry support the importance of a low-fat diet
for long-term weight management.335 Participants in
this registry, which is comprised of obese persons who
have maintained a weight loss of ⱖ14 kg (30 pounds) for
at least 1 year (average weight loss of 29 kg maintained
for 6.9 years), reported consuming less than 25% of
calories from fat.
Energy density. The beneficial effects of a low-fat
diet on body weight may be related to the effect of fat on
energy density. Dietary fat content and energy density,
defined as the energy (i.e., calories) present in a given
weight (g) of food, are highly correlated because fat has
such a high energy density. A series of elegant, but
short-term (up to 14 days), studies have demonstrated
that energy intake is regulated by the weight of ingested
food, rather than by fat or energy content.336 In one
study, both lean and obese subjects given either an ad
libitum high-fat/high-energy-density (1.5 kcal/g) diet or
a low-fat/low-energy-density (0.7 kcal/g) diet ate the
same weight of food, so energy intake on the high-fat/
high-energy-density diet (3000 kcal/day) was almost
twice that consumed on the low-fat/low-energy-density
diet (1570 kcal/day).337 In other studies, subjects who
were given liquid diets that varied in fat content (from
20% to 60%) but had the same energy density also ate
the same weight of food, so total energy intake was the
same despite large differences in fat intake.338 –341 Finally, several studies have found that the same weight of
food is eaten when energy density is manipulated while
keeping fat content the same. Therefore, energy intake
was inversely correlated with energy density, and subjects who consumed a low-energy-density diet lost
weight.341,342 These data demonstrate that dietary fat
content itself does not affect total energy intake, independent from its effects on diet energy density and food
palatability. The results of short-term studies suggest
that manipulating energy density might be a useful
approach to regulate total energy intake. However, longterm studies in obese subjects are still needed to confirm
that low-energy-density diets can help induce and maintain weight loss.
The energy density of a diet can be decreased by
adding water to food, increasing the intake of highwater-content foods, such as fruits and vegetables, and by
limiting the intake of high-energy-density foods, such as
high-fat and dry foods (e.g., crackers and pretzels). The
energy density of some low-fat dry foods (e.g., fat-free
pretzels) is as high as that of some high-fat foods (e.g.,
cheese) (Figure 5). Surprisingly, consuming water with a
meal may not have the same effect as adding water to the
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AMERICAN GASTROENTEROLOGICAL ASSOCIATION
Figure 5. Energy density of selected commonly consumed foods.
Foods that have a high fat content usually have a high energy density,
whereas foods that have a high water content usually have a low
energy density. (Figure provided courtesy of Liane Roe.)
food itself. In one study, eating chicken rice soup before
lunch caused a greater decrease in the consumption of
lunch calories than eating chicken rice casserole (same
calories but greater energy density) or chicken rice casserole with 356 mL of water (same calories and same
amount of water).343 These data suggest that adding
water to a food influences food intake by its effect on
sensory and cognitive factors rather than by its effect on
gastric volume.
Low-carbohydrate diets. Recently, there has been
a renewed interest in the use of low-carbohydrate diets
for losing weight. Although these diets were introduced
more than 100 years ago to treat obesity,344 and different
variations with their own labels continue to resurface,
there is a paucity of data from clinical trials of the
long-term efficacy of low-carbohydrate diets in obese
persons. Several randomized345–347 and nonrandomized348 controlled trials have compared the weight loss
effect of short-term (ⱕ12 week) low-carbohydrate with
high-carbohydrate diets, when energy intake was identical in both groups. The results from these studies
suggest that early (ⱕ4 week) weight loss can be greater
with a low- than a with a high-carbohydrate diet despite
the same energy intake because of greater water losses in
the low-carbohydrate group. However, weight loss between 6 and 12 weeks of treatment is likely to be the
same for subjects consuming either diet when energy
intake is identical.
Many of the current popular low-carbohydrate diets
limit carbohydrate intake (e.g., the Atkins diet limits
carbohydrate intake to 20 g/day349), but allow unre-
GASTROENTEROLOGY Vol. 123, No. 3
stricted amounts of fat and protein. The authors of
low-carbohydrate diet books often provide anecdotal case
studies to support their diets and have proposed several
implausible metabolic mechanisms to explain how their
diets cause weight loss. Nonetheless, there may be valid
explanations for how low-carbohydrate diets with ad
libitum fat and protein intake can generate weight loss,
including (1) initial diuresis associated with ketone and
urea nitrogen excretion,345 (2) losses of up to 100 kcal/
day in urinary ketones,344 and (3) decreased energy intake, possibly related to ketosis, diet monotony, or other
unknown mechanisms. Two recent prospective trials reported that when obese subjects restrict their carbohydrate intake they do not completely compensate for the
energy deficit by increased consumption of fat and protein.350,351 In one study, total energy intake decreased by
approximately 1000 kcal/day after obese subjects started
a low-carbohydrate, ad libitum fat and protein intake
diet.350 In a second study, obese subjects lost 10% of
their initial body weight 6 months after starting the
Atkins diet.351 To date, one randomized controlled trial
has evaluated the effectiveness of the Atkins diet.352 At
the end of 12 weeks, average weight loss was 3.4% in the
Atkins diet group and 8.6% in the traditional highcarbohydrate, low-fat diet group. No randomized controlled trials evaluating the long-term effectiveness of a
low-carbohydrate diet have been reported.
The possibility that low-carbohydrate with ad libitum
fat and protein diets could have harmful effects has not
been carefully studied. It has been suggested that highfat and high-protein intake could cause dehydration,
electrolyte imbalance, hyperuricemia, calciuria, kidney
stones, glycogen depletion with easy fatigue, and hyperlipidemia.344 However, no serious adverse effects were
reported in 41 subjects who completed a 6-month trial of
the Atkins diet.351 In fact, these subjects experienced a
7% decrease in plasma LDL cholesterol, a 43% decrease
in plasma triglycerides, and an 18% increase in plasma
HDL cholesterol. Additional long-term studies containing large numbers of subjects are needed to determine
whether low-carbohydrate diets could ultimately result
in net harm.
Physical Activity
Body Composition
The addition of exercise training to a diet program can affect the composition of weight loss. Two
meta-analyses that pooled data from 4682 and 28353
published trials found that exercise can attenuate the loss
of FFM. Regular low- or moderate-intensity exercise
decreased the percentage of weight lost as FFM by half,
September 2002
from approximately 25% to 12%, when diet-induced
weight loss was ⬃10 kg. However, this large difference
in percentage of weight lost as FFM represented only a
small (⬃1 kg) difference in the absolute amount of FFM
lost between groups. Moreover, conservation of FFM does
not necessarily represent conservation of muscle protein;
the greater retention of FFM associated with exercise may
be related to increased retention of body water and
muscle glycogen. In fact, nitrogen balance studies in
women have failed to show any nitrogen-sparing effect of
exercise during diet-induced weight loss.354 It is not
clear whether there is a difference between endurance and
resistance exercise in FFM conservation because of limited and conflicting data.355,356
Metabolic Rate
Although exercise has a profound effect on energy
expenditure during the actual bout of exercise, the results from most studies suggest that adding regular
exercise to a reduced-calorie diet program has little, if
any, effect on REE. A meta-analysis of prospective controlled trials that randomized obese subjects to diet alone
or diet plus exercise found that exercise training did not
prevent the expected decline in REE, when REE was
adjusted for loss of body mass.357
Weight Loss
Physical activity alone is not an effective method
for achieving initial weight loss. The energy deficit generated by physical activity in obese persons is usually
much less and requires more effort than the energy deficit
generated by a reduced-calorie diet. For example, walking or running 1 mile consumes about 110 kcal of
endogenous fuel. Therefore, the loss of 2 pounds per
week that typically is induced by a 1000-kcal/day deficit
diet would require walking or running 65 miles per week
if energy intake remained constant. The results from
most studies have shown that moderate endurance exercise such as brisk walking for 45 to 60 minutes 4 times
a week for up to 1 year usually induces a weight loss of
only a few kilograms.353,358,359
Adding a regular exercise program to short-term (ⱕ6
months) diet intervention does not increase initial
weight loss significantly358 unless it is prolonged and
vigorous activity (e.g., 88 minutes per day of brisk
walking or cycling).360 Moreover, the type of exercise
performed while dieting does not seem to make a difference. In one prospective randomized trial, obese subjects
who consumed a 925-kcal/day diet for 4 months lost the
same amount of weight whether they were assigned to
diet alone, diet plus endurance training, diet plus
AMERICAN GASTROENTEROLOGICAL ASSOCIATION
901
strength training, or diet plus both endurance and
strength training.355
Weight Maintenance
Although increasing physical activity is not effective for initial weight loss, physical activity is very
important for long-term weight management. Several
large-scale cross-sectional case studies found that obese
subjects who achieved successful long-term (ⱖ1 year)
weight loss participated in regular exercise.335,361–363
Retrospective analyses of prospective clinical weight loss
trials also found that subjects who reported exercising
regularly maintained their weight losses significantly
better than those who remained sedentary.364,365 In addition, several prospective randomized studies found that
subjects assigned to diet-plus-exercise conditions who
continued to exercise maintained substantially larger
weight losses than those randomized to diet alone or to
diet plus exercise but who stopped exercising.366 –369
Nonetheless, most prospective randomized trials failed to
find a statistically significant long-term beneficial effect
of exercise on body weight when data were analyzed on
an intention-to-treat basis, presumably because many
subjects failed to adhere to their exercise program.358 The
beneficial effect of exercise on long-term body weight
probably involves both physiological and psychological
mechanisms. Physical activity can help prevent weight
regain by consuming energy and by enhancing selfesteem and mood, which may improve dietary compliance and the ability to cope with eating-related situations.370
The amount of physical activity required to maintain
weight loss appears to be much greater than that recommended by the American College of Sports Medicine and
the Centers for Disease Control and Prevention for good
health.371 Recent studies indicate that obese patients
should expend approximately 2500 kcal/week to maintain weight loss.335,372–374 This amount of energy expenditure can be achieved by moderate activity (brisk walking) for approximately 60 to 75 minutes per day or by
more vigorous activity (aerobics, cycling, or jogging) for
30 minutes per day. For most obese persons, this level of
activity cannot be reached in a short period of time, so it
is important to set modest activity goals initially and
increase activity slowly over time. Pedometers provide a
reliable and inexpensive method of tracking most forms
of physical activity.375 A reasonable goal is to increase the
number of steps walked daily by 1000 every month until
reaching a total of 15,000 steps per day (equal to approximately 60 to 75 minutes or 3 to 4 miles of walking
per day).
902
AMERICAN GASTROENTEROLOGICAL ASSOCIATION
The greatest hurdle to increasing long-term physical
activity is compliance. This problem has led to evaluation of the merits of programmed vs. lifestyle activities.
Programmed activity consists of regularly scheduled
bouts of running, swimming, cycling, and other aerobic
activities, which usually are engaged in for a discrete
period of time (e.g., 30 to 60 minutes) at a relatively
high intensity level (e.g., 60% to 80% of maximum
heart rate). Lifestyle activity involves increasing energy
expenditure during the course of the day by practices
such as walking rather than riding, using stairs rather
than escalators, and discarding energy-saving devices
such as television remote controls and extension telephones.
Two approaches may improve adherence to programmed activity. The first is to divide one long bout of
exercise activity into several shorter bouts for those who
“can’t find the time to exercise.” In one prospective trial,
obese women randomized to 3 short (10 minutes) bouts
of aerobic exercise (primarily walking) per day, 5 days
per week, reported 20% more exercise time per week
than obese women randomized to the same total amount
of activity but in long (30 minutes) bouts of aerobic
exercise per day, 5 days per week.376 There was also a
trend toward greater weight loss in the short-bout exercise group. A second method of facilitating exercise
adherence is to have patients exercise at home rather than
at a health club or similar facility because home exercise
is associated with fewer barriers, including costs and
travel time. Two prospective randomized trials found
that both adherence to a walking program377,378 and
maintenance of weight loss378 were significantly better at
1 and 2 years in subjects who were assigned to walk at
home compared with those who participated in a supervised on-site program. The use of home exercise equipment, such as a treadmill, has also been shown to improve exercise adherence and long-term weight loss.373
Altering lifestyle activity without emphasizing work
intensity may provide more opportunities for increasing
physical activity than programmed exercise. In children,
instruction in increasing lifestyle activity was associated
with significantly better maintenance of weight loss than
participation in programmed exercise.379,380 A recent
study in obese adults found that weight loss was the same
after a 16-week behavioral program that combined a
1200 kcal/day diet with either lifestyle activity or programmed exercise.381 There was also a trend toward
better maintenance of weight loss 1 year after treatment
in the lifestyle activity participants than in the group
that received programmed exercise. Moreover, there was
a direct relationship between level of activity and weight
GASTROENTEROLOGY Vol. 123, No. 3
maintenance. These findings demonstrate that education
to alter lifestyle activities is a reasonable alternative to
programmed exercise for properly selected obese patients.
Additional health benefits of physical activity.
Aerobic exercise has additional health benefits that are
independent of weight loss itself. Endurance exercise
increases insulin sensitivity and aerobic fitness.382 Increased physical activity and aerobic fitness are associated
with a decreased risk of developing diabetes22,383 and
dying from cardiovascular disease.23 In fact, the risks of
cardiovascular and all-cause mortality are lower in fit
obese men than in unfit lean men (Figure 6).23 A large
number of studies also have demonstrated psychological
benefits of exercise in nonobese individuals. Surprisingly,
there have been few studies of the psychological effects of
exercise in obese persons.384 In the largest investigation
to date, subjects treated by diet plus aerobic activity had
significant reductions in depression and fatigue and improvements in vigor.355 However, improvements in psychological functioning were no greater in these participants than in those who lost weight by diet alone.
Behavior Modification
The purpose of behavior modification therapy is
to help patients identify and then modify eating and
Figure 6. Relative risk (RR) of cardiovascular disease (CVD) mortality,
stratified by body fatness and cardiorespiratory fitness in men. Body
fat categories were classified by percentage body fat according to
percentile scores: lean (⬍16.7% body fat; ⬍25th percentile), normal
(16.7%–24.9% body fat; 25th to ⬍75th percentile), and obese (ⱖ25%
body fat; ⱖ75th percentile). Cardiorespiratory fitness was determined
by oxygen consumption during a maximal treadmill exercise test. Unfit
men (black bars) were defined as those who were in the lowest
quartile (20%) of oxygen uptake (expressed as mL consumed/kg
FFM/min) in each age group; all other men were considered fit (white
bars). (Reprinted with permission from Lee et al.23 © Am J Clin Nutr.
American Society for Clinical Nutrition.)
September 2002
physical activity habits that contribute to their obesity.
This approach is based on the classical conditioning
principle that behaviors often are prompted by an antecedent event, and the link between the antecedent event
and the behavior becomes stronger with repetition. For
example, eating may be triggered by watching television.
The more often the two events are paired together, the
stronger will be the connection between them; eventually the presence of one automatically triggers the other.
Eating often is the consequence of a series of antecedent
events. Many factors may contribute to overeating as
illustrated in the behavior chain in Figure 7. Disconnecting triggers within the chain (e.g., instructing the patient to limit all eating at home to the kitchen and
dining room to break the link between eating and television viewing) will diminish the strength of each trigger
over time. In addition, a cognitive component is included in behavioral treatment because it is believed that
thoughts (or cognitions) directly affect feelings and behaviors. Therefore, how patients perceive a specific situation will influence their feelings about it and their
desire for change.
Principles of Therapy
There are 3 general principles of behavior modification therapy. First, behavioral treatment is goaldirected and specifies goals in terms that can be easily
measured. This is true whether the goal is walking for 20
minutes 3 times per week, limiting the consumption of
a specific food to 2 portions per week, or decreasing the
number of self-critical comments. Providing specific
Figure 7. Example of a behavior change that demonstrates how
individual behaviors are linked together to contribute to an episode of
overeating. Therefore, dietary indiscretion can be traced to a series of
small decisions and behaviors. (Reprinted with permission from
Brownell KD. Sample behavioral chain. The LEARN Program for weight
management–2000. Dallas, Texas: American Health Publishing Company; 2000:204. All rights reserved. For ordering information, call
1-888-LEARN-41 or visit www.TheLifeStyleCompany.com.
AMERICAN GASTROENTEROLOGICAL ASSOCIATION
903
goals facilitates the assessment of goal attainment and
the initiation of targeted problem solving.
Second, behavioral treatment is process-oriented and
helps patients develop realistic goals and a reasonable
plan for reaching those goals. Therefore, once a specific
goal is identified, patients are encouraged to examine
factors that will help or hinder goal achievement and to
develop strategies for success. This philosophy holds that
planning, not willpower, is the key to weight management.
Third, behavioral treatment advocates making small
rather than large changes. This is based on the learning
principle of successive approximation in which incremental steps are taken to achieve more distant goals.
Setting small and achievable goals allows patients to have
successful experiences, which can be used as a foundation
for additional lifestyle alterations. Drastic behavior
change is usually short-lived.
Components of Therapy
Behavior therapy of obesity usually includes multiple components: self-monitoring (daily records of food
intake and physical activity), stimulus control (avoiding
triggers that prompt eating), social support (assistance
from family members and friends in modifying lifestyle
behaviors), cognitive restructuring (thinking in a positive manner), problem-solving skills (systematic methods of analyzing problems and identifying possible solutions), and relapse prevention (methods to help recovery
from episodes of overeating or weight regain).385 These
strategies are used to modify eating and activity habits.
Self-monitoring (i.e., recording one’s behavior) is the
cornerstone of behavioral treatment, and several studies
have shown that it correlates with successful long-term
weight control.386 At first, patients keep daily records of
their food intake, including the type, amount, and energy content, without attempting to change their diet.
Dietary advice is then given to reduce energy intake by
a specific amount (usually 500 –1200 kcal/day) to achieve
a gradual rate of weight loss per week (usually 1 pound
per week). Record keeping is expanded over time to
include information about times, places, and feelings
associated with eating. These records provide the information needed to identify different components of the
behavior chain that can be targeted for intervention.
Accurate record keeping also serves to decrease, although
not eliminate, the tendency to underestimate food intake.387
The behavioral approach to physical activity supports
the notion that any activity is better than none. Efforts
are directed toward increasing activity gradually along a
continuum, rather than initially targeting a specific ac-
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GASTROENTEROLOGY Vol. 123, No. 3
tivity “threshold” (e.g., 30 minutes of walking at 80% of
maximum heart rate). This can be accomplished by increasing programmed or lifestyle activity or both. Clinical experience suggests that lifestyle activity provides an
excellent alternative for obese persons who “hate to exercise.”
Cognitive restructuring is an important component of
behavior therapy because it teaches patients to identify,
challenge, and correct the irrational thoughts that frequently undermine weight control efforts. These thoughts
usually occur when there are setbacks in maintaining
dietary control and when desired weight loss is not
achieved. Cognitive restructuring teaches patients to
avoid the extremes of catastrophizing (“I’ve blown it”)
and denial (“It’s nothing to worry about”), neither of
which is helpful for long-term weight control. Cognitive
techniques also can help patients accept weight losses
that are less than desired but still medically beneficial.
Developing realistic goals and responses to counter unrealistic cognitions (e.g., “I won’t be happy until I can
wear a size 6 dress”) are important to prevent a feeling of
failure, which can lead to relapse and weight regain.
Treatment structure. Behavior therapy can be
provided in either group or individual sessions. Although obesity is a chronic illness, behavior treatment
usually is provided in a time-limited fashion, with predetermined starting and finishing dates, often lasting 16
to 26 weeks.388 There have been no controlled comparisons of the effects on long-term weight loss of timelimited vs. open-ended treatment.
Clinical effectiveness. Patients treated by a comprehensive group behavior therapy approach lose about
9% of their initial weight in 20 to 26 weeks of treatment.389 Table 7 summarizes the results of prospective
randomized clinical trials published in 4 leading behavioral journals from 1974 to 1995 that evaluated the
effectiveness of behavior therapy in achieving weight
Table 7. Summary of Randomized Clinical Trials of Group
Behavior Therapy for Weight Loss
1974 1984 1990–1995 1996–1999
Number of trials
15
15
Treatment duration (wk)
8
13
Rate of weight loss (kg/wk)
0.5 0.5
Weight loss (kg)
3.8 6.9
Length of follow-up (wk)
6
58
Weight loss at follow-up (kg) 4.0 4.4
14
26
0.4
9.0
40
5.2
9
21
0.5
9.6
74
6.0
All trials evaluated in this Table were published in Addictive Behaviors,
Behavior Therapy, Behaviour Research and Training, and Journal of
Consulting and Clinical Psychology. Values represent the means
across studies, weighted by the number of subjects in each study.
Data from Wadden TA, Foster GD. Behavioral treatment of obesity.
Med Clin North Am 2000;84:441– 461.
loss. Although the mean weekly rate of weight loss
remained the same (⬃0.5 kg per week), total weight loss
induced by behavior therapy more than doubled over this
20-year period because treatment duration doubled.
Weight regain is common after treatment ends. As
shown in Table 7, patients typically regain about 30% to
35% of their lost weight in the year following treatment.
Nonetheless, most patients still maintain medically significant weight loss of ⱖ5% of initial body weight at the
end of 1 year.
Efforts to increase total weight loss by increasing the
duration of behavior therapy have been only marginally
successful. In 2 studies, weekly treatment was provided
for 1 year with the expectation that subjects would lose
an average of 0.5 kg/week or 25 kg (⬃25% of body
weight).316,390 Average weight loss at 1 year, however,
was only ⬃14 kg and was achieved within the first 6
months of therapy. Nonetheless, continued therapy probably prevented weight regain that usually occurs after
treatment is stopped. In a series of studies, Perri et
al.391–393 reported that obese patients who maintained
regular biweekly contact with their treatment providers– by telephone, postcards, or in-clinic visits–maintained their full end-of-treatment weight loss for as long
as such care was provided. Unfortunately, when contact
was withdrawn, patients began to regain weight. These
data demonstrate that prolonged treatment is needed to
achieve long-term weight management success. Moreover, the benefit of long-term therapy is to improve
weight maintenance rather than increase the magnitude
of weight loss.
Practical considerations. Although long-term
group behavior therapy is effective, it is not widely
available, so finding a suitable provider can be problematic. Even when a good obesity-behavior therapy program can be identified, it may be unaffordable for many
patients because insurance carriers usually do not reimburse treatment. In addition, patients often tire of behavioral treatment after the first 6 to 12 months and it is
difficult to maintain long-term interactions. Several
studies found that patients attended approximately half
as many sessions during the last several months of treatment as compared with the first several months.316,394
Recent data suggest that the Internet might provide a
valuable resource for facilitating patients’ adherence to
appropriate diet and activity regimens. Participants in a
pilot study lost 4.1 kg in 12 weeks, a loss only slightly
smaller than that produced with traditional group behavior therapy.395
Providing appropriate behavior modification therapy
for obesity within a clinical practice is difficult because
September 2002
physicians usually do not have the time or expertise to
provide such care. Patients are likely to obtain the best
results when they are seen frequently, such as every week
or every other week. The anticipation of “weighing-in”
and having to submit food records provides important
motivation. Some physicians may be able to enlist the
support of a nurse, medical technician, or dietitian who
could weigh patients, briefly review their food records,
and praise their efforts.
Alternatively, the physician may refer the patient to a
legitimate commercial or self-help program. Weight
Watchers, for example, is reasonably priced and provides
social support and sound advice on nutrition, exercise,
and behavior modification. Take Off Pounds Sensibly
(TOPS) is a self-help program that takes a similar approach. Overeaters Anonymous is another self-help option, which is appropriate for persons who binge eat or
wish to explore emotional issues related to weight and
eating. If patients are referred out, the physician should
support their weight loss efforts by asking to see their
weight graphs or food records and by inquiring about
satisfaction with treatment.
Pharmacotherapy
General Principles
The difficulty in achieving long-term weight
management with lifestyle modification has led to an
increased interest in pharmacotherapy for obesity. Although pharmacotherapy can help selected patients
maintain long-term weight loss, 7 issues regarding the
use of drugs should be considered. First, the greatest
problem in obesity therapy is the high rate of relapse, so
the most important challenge of pharmacotherapy is to
maintain long-term weight loss. Therefore, it is inappropriate to consider the use of pharmacotherapy as a shortterm approach to “get patients going,” because patients
who respond to drug therapy usually regain weight when
therapy is stopped.396 –398 Effective pharmacotherapy for
obesity is likely to require long-term, if not lifelong,
treatment. Second, the required chronicity of drug treatment for obesity makes it particularly important to
analyze carefully the long-term risks of obesity, the beneficial effects of pharmacotherapy on body weight and
obesity-associated diseases, and the side effects and costs
of treatment. This analysis is difficult because no prospective randomized controlled trials have evaluated the
efficacy of any currently approved drugs for obesity for
longer than 2 years. Third, some patients are refractory to
drug therapy. If a patient does not respond to drug
treatment for obesity in the first 4 weeks, long-term
success is unlikely399,400 and discontinuation of treat-
AMERICAN GASTROENTEROLOGICAL ASSOCIATION
905
ment should be considered. Fourth, drug therapy does
not cause an indefinite reduction in body weight; weight
loss usually plateaus by 6 months of treatment. Compared with placebo, drug therapy delays the onset and
the level at which a plateau in weight loss occurs. Body
weight begins to increase after ⬃1 year, despite continued drug treatment, but weight regain is less with drug
than placebo.397,401 Therefore, overall weight loss observed in drug-treated patients is still greater than that
observed in placebo-treated patients at 2 years. These
data demonstrate that pharmacotherapy alone is unable
to maintain a long-term plateau in body weight and
suggest that either the effectiveness of medication diminishes over time or obesity is a continuously progressive disease, or both. Fifth, pharmacotherapy is not a
“cure” for obesity; current medications have clinically
significant but moderate effects on body weight and
obesity-associated diseases. At the end of 1 year of treatment, the best of the currently available medications
increases average weight loss by several percentage points
and may double the number of patients who achieve a
clinically significant weight loss (ⱖ10%).397,401 Sixth, it
is difficult to judge the effectiveness of medications that
were approved by the United States Food and Drug
Administration (USFDA) for obesity treatment more
than 5 years ago (no medications were approved between
1974 and 1996). The criteria required to approve antiobesity agents were much less stringent in the past than
they have been in the last 5 years; earlier trials contained
considerably fewer subjects and were much shorter than
more recent studies. Seventh, pharmacotherapy alone is
not as effective as pharmacotherapy given in conjunction
with a comprehensive weight-management program
(Figure 8).402,403 Therefore, patients given drug treatment without the other standard approaches to weight
management, including behavior modification, diet education, and exercise counseling, are exposed to the full
risks of drug treatment without the full medical benefits.
Criteria for success. To evaluate the effectiveness
of drug therapy, it is important to establish criteria for a
successful treatment outcome. A clinically useful definition of a successful outcome might be individualized for
each patient and, therefore, could involve a range of end
points, such as amount of weight loss, prevention of
weight gain, slowing the rate of future weight gain,
improvement of obesity-associated medical complications, and improvements in quality of life and function.
A reasonable and medically significant outcome for many
patients is to lose 10% of body weight in the first 6
months of treatment.
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AMERICAN GASTROENTEROLOGICAL ASSOCIATION
Figure 8. Weight loss in women treated with anorexiant medication
(sibutramine) alone (diamonds), medication plus group behavior modification therapy (squares), or medication plus group behavior modification therapy and meal replacements (triangles). These data demonstrate that greater weight loss is achieved when anti-obesity
medications are used in conjunction with lifestyle modification than
when they are used alone. (Reprinted with permission from Wadden et
al.403 Arch Intern Med 2001;161:218 –227. Copyrighted 2001, American Medical Association.)
Criteria for approval of new anti-obesity medications. The USFDA has proposed that drugs approved for
the treatment of obesity demonstrate in a 1-year randomized, double-blind, controlled trial that: (1) weight loss
with drug treatment is more than 5 percentage points
greater than, and statistically significantly different from,
weight loss with placebo; and (2) compared with placebo,
drug treatment causes a statistically significantly larger
number of subjects to achieve a ⬎5% weight loss.404,405
It is also recommended that studies be performed in year
2 to demonstrate maintenance of weight loss, but there is
no proposal for longer studies. However, evaluating the
effectiveness of a drug in a randomized controlled clinical
trial can be confounded by the choice of adjunctive
obesity therapy that is provided as part of the study
protocol. Weight loss achieved in placebo-treated groups
can vary widely, depending on the type of diet, exercise
prescription, and behavior therapy program that is incorporated into the study.406 An effective obesity treatment program will minimize differences between drug
and placebo-treatment groups and make seeing an additional effect of a drug on body weight more difficult.
Overview of medications and mechanisms of action. Medications approved by the USFDA for the treat-
ment of obesity are listed in Table 8. Only sibutramine
and orlistat are approved for long-term use. With the
exception of orlistat, which inhibits the absorption of
dietary fat, all medications approved for obesity treatment act as anorexiants. Methamphetamine and benz-
GASTROENTEROLOGY Vol. 123, No. 3
phetamine are addictive and should be avoided. Recently, 3 anorexiant medications have been removed
from the marketplace because of increased risks of
either valvular heart disease (fenfluramine and dexfenfluramine)407 or hemorrhagic stroke (phenylpropanolamine)408 associated with their use.
Anorexiant medications increase satiation (level of
fullness during a meal, which regulates the amount of
food consumed), or satiety (level of hunger after a meal is
consumed, which regulates the frequency of eating), or
both, by affecting the monoamine (norepinephrine, serotonin, and dopamine) system in the hypothalamus. All
of the anorexiant medications, with the exception of
mazindol, are derivatives of the amphetamine precursor
␤-phenylethylamine. Methamphetamine is addictive and
should be avoided, whereas the other amphetamine derivatives have been chemically modified to reduce abuse
potential. Monoamine neurotransmitters are synthesized
from tyrosine and stored in granules that release their
contents from presynaptic nerve terminals into the interneuronal cleft between presynaptic and postsynaptic
nerves. Most of the monoamines released into the interneuronal cleft are taken back up into the presynaptic
nerve terminal, where they are either degraded or repackaged into granules for future release. A small portion of
released monoamines bind to postsynaptic receptors,
Table 8. Drugs Approved by the United States Food and
Drug Administration for the Treatment of Obesity
Generic name
Methamphetamine
hydrochloridea
Benzphetamine hydrochlorideb
Phendimetrazine tartratec
Phentermine
Hydrochlorided
Resine
Diethylpropion hydrochloride
Immediate releasef
Controlled releasef
Mazindolg
Sibutramine hydrochloridea
Orlistath
aAbbott,
Trade name(s)
Desoxyn
15
Didrex
Bontril, Plegine,
Prelu-2, X-Trozine
25–150
70–210
Adipex-P, Fastin,
Oby-trim
Ionamin
15–37.5
Tenuate
Tenuate Dospan
Sanorex, Mazanor
Meridia
Xenical
Chicago, IL.
& Upjohn, Kalamazoo, MI.
cAmarin, Warren, NJ.
dGate, Sellersville, PA.
eCelltech, Rochester, NY.
fWatson, Corona, CA.
gWyeth-Ayerst, Philadelphia, PA.
hRoche Laboratories, Nutley, NJ.
bPharmacia
Daily
dose
(mg)
15–30
75
75
1–3
5–15
360
September 2002
thereby transmitting a signal from one nerve to the
other.
The 2 most commonly prescribed anorexiants are
phentermine and sibutramine. Phentermine stimulates
the release of norepinephrine and dopamine from nerve
terminals. Sibutramine inhibits the reuptake of norepinephrine, serotonin, and, to a lesser degree, dopamine.
Sibutramine affects satiation, rather than satiety, and
may also cause a small increase in metabolic rate several
hours after its administration in humans.409
Orlistat is a synthetic derivative of lipstatin, a product
made by the Streptomyces toxytricini mold, which inhibits
most mammalian lipases.410 When ingested, orlistat
binds to gastric, pancreatic, and carboxylester lipases in
the gastrointestinal tract and blocks the action of these
lipases on dietary triglycerides and vitamin esters. The
inhibition of fat digestion decreases micelle formation
and the absorption of long-chain fatty acids, cholesterol,
and certain fat-soluble vitamins. The percentage of malabsorbed fat is directly related to drug dose in a curvilinear fashion (Figure 9).411 At a dose of 360 mg/day
(120 mg 3 times daily with meals), ⬃30% of ingested
triglycerides are excreted in stool, which is near the
maximum plateau value. Therefore, ingesting more than
120 mg of orlistat with a meal is unlikely to increase the
malabsorption of ingested fat appreciably.
The large range in fat malabsorption at any given
orlistat dose (shown in Figure 9) is presumably a function
of how well orlistat mixes and remains with the fat
content of the meal. After ingestion of a meal plus
Figure 9. Dose-response relationship between orlistat treatment and
fecal fat excretion. Data from individual subjects (open circles) and
the curve that best fits the data (continuous line) are shown. Fat
malabsorption increased sharply with increasing orlistat dose, up to a
near plateau value of 360 mg/day (120 mg 3 times daily with meals).
(Reprinted with permission from Zhi et al.411)
AMERICAN GASTROENTEROLOGICAL ASSOCIATION
907
orlistat, fat is released slowly from the stomach, while
orlistat empties more rapidly.412 Therefore, orlistat may
bind only to lipases released during the early portion of
a meal and may not be available when the remaining
portion of ingested fat enters the duodenum. Enhancing
the physical interaction between orlistat and ingested fat
increases orlistat’s malabsorptive potency. A 4-hour duodenal perfusion of orlistat during the oral consumption
of a test meal containing 10 g of fat and a 4-hour
duodenal perfusion of a lipid emulsion containing 30 g of
fat resulted in ⬎95% inhibition of triglyceride hydrolysis.413 Less than 1% of ingested orlistat is absorbed;
therefore, it has no effect on systemic lipases.414
In general, the approved indications for pharmacotherapy for obesity are a BMI ⱖ30 kg/m2 or a BMI between
27 and 29.9 kg/m2 in conjunction with an obesityrelated medical complication, in patients who have no
contraindications to therapy. A comprehensive review of
drug therapy for obesity was published recently.405 Only
the data from long-term (defined as ⬎6 months) prospective, randomized, controlled trials that evaluated the
weight loss efficacy and side effects of the most commonly prescribed medications will be reviewed here.
Phentermine. Only one prospective randomized
controlled trial has evaluated the effect of at least 6
months of phentermine therapy on body weight.415 In
that study, which was published in 1968, 108 obese
women were randomized to receive a 1000 kcal/day diet
and treatment with either daily phentermine, daily
phentermine every other month alternating with daily
placebo every other month, or daily placebo for 36 weeks.
Of the 64 subjects who completed the study, weight loss
in the groups receiving continuous or alternating phentermine (with placebo) therapy were the same (13% of
initial weight), and greater than the loss observed in the
placebo group (5% of initial weight).
Phentermine side effects. The most common
side effects of phentermine are related to its sympathomimetic effects and include dry mouth, insomnia, and
constipation. Although all sympathomimetic agents can
increase blood pressure and heart rate, these abnormalities usually do not occur with phentermine therapy in
the presence of weight loss.
Sibutramine. Treatment with sibutramine at
doses between 1 and 30 mg per day for 24 weeks
demonstrated that weight loss was clearly dose-dependent, ranging from 0.9% to 7.7% of initial body weight
for placebo and 30 mg per day, respectively.396 The
current recommended starting dose is 10 mg per day,
which can be decreased or increased by 5 mg in those
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AMERICAN GASTROENTEROLOGICAL ASSOCIATION
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Table 9. Summary of 1-year, Randomized, Controlled Trials That Compared Sibutraminea or Orlistatb With Placebo
Weight loss at 1 year
Mean
(% initial
weight)
First author (ref)
Year
No. of
subjects
randomized
Sibutramine trials
Smith417
McMahon418
2001
2000
485
224
1.8
0.7
Orlistat trials
Sjöström397
Davidson420
Rossner290
Finer421
Hauptman422
1998
1999
2000
2000
2000
688
892
487
228
422
Lindgarde424
2000
Hollander423
1998
Placebo
ⱖ5%
(% subjects)
Drug
ⱖ10%
(% subjects)
Placebo
Drug
Placebo
Drug
Site
Comments
7.3
4.7
20
9
57
40
7
4
34
13
United Kingdom
United States
Mean BMI ⫽ 33 kg/m2
BMI ⫽ 27–40 kg/m2
HTN
6.1
5.8
6.6
5.4
4.2
10.2
8.8
9.8
8.5
7.9
49
44
44
21
31
69
66
63
35
51
18
25
19
17
11
39
39
38
28
29
Europe
United States
Europe
United Kingdom
United States
376
4.6
5.9
41
54
15
19
Sweden
391
4.3
6.2
23
49
9
18
United States
BMI ⫽ 28–47 kg/m2
BMI ⫽ 30–43 kg/m2
BMI ⫽ 28–43 kg/m2
BMI ⫽ 28–43 kg/m2
BMI ⫽ 28–43 kg/m2
Primary care setting
BMI ⫽ 28–38 kg/m2
Type 2 DM, HTN,
dyslipidemia
Primary care setting
BMI ⫽ 28–40 kg/m2
Type 2 DM
DM, diabetes mellitus; HTN, hypertension.
15–20 mg day.
bOrlistat, 120 mg 3 times daily.
aSibutramine,
who do not tolerate or who do not respond adequately to
the initial dose.416
Two prospective 1-year randomized controlled trials
have been reported that evaluated the efficacy of sibutramine therapy in producing and maintaining weight loss
(Table 9).417,418 In both trials, more subjects randomized to 10 to 20 mg/day of sibutramine lost ⱖ5% and
ⱖ10% of their initial weight than those in the placebo
group. Minimal adjunctive weight management therapy
was provided, so the placebo group achieved less weight
loss than that usually observed in placebo groups from
other trials. The results from another study demonstrated
that weight loss with intermittent sibutramine therapy
(15 mg/day given during weeks 1 through 12, 19
through 30, and 37 through 48, and placebo administered during the other weeks) was equivalent to weight
loss with continuous sibutramine therapy (15 mg/
day).418a
Two prospective randomized controlled trials have
evaluated the efficacy of sibutramine therapy in longterm weight management after a predetermined amount
of weight loss was achieved initially.401,419 In one study,
160 obese subjects who lost 6 kg or more after 4 weeks
of treatment with a VLCD resumed a regular diet with
diet counseling and were randomly assigned to 1 year of
treatment with placebo or sibutramine (10 mg/day) therapy.419 In the year after randomization, subjects given
sibutramine lost an additional 5.2 kg (total study weight
loss of 12.9 kg), whereas those in the placebo group
gained 0.5 kg (total study weight loss of 6.9 kg). Among
subjects treated with sibutramine, 74% maintained or
increased the weight loss achieved with a VLCD, compared with 41% of placebo-treated patients. In the second study, 467 obese subjects who experienced more
than a 5% weight loss at the end of 6 months of
treatment with sibutramine (10 mg/day) and a 600
kcal/day deficit diet were randomized to 18 months of
dietary counseling and treatment with either sibutramine (increased to 15 or 20 mg/day) or placebo.401
Almost half of the subjects who entered the study
dropped out before completing the 18-month treatment
program. On average, those randomized to sibutramine
treatment maintained their weight loss for 1 year, followed by a slight and progressive increase in weight
thereafter; those randomized to placebo treatment experienced a progressive increase in weight as soon as they
stopped sibutramine therapy. Of the subjects who completed the study, 43% of sibutramine-treated and 16%
of placebo-treated subjects maintained 80% or more of
their original 6-month weight loss.
Sibutramine side effects. The most common side
effects associated with sibutramine therapy are dry
mouth, headache, constipation, and insomnia, which are
usually mild and transient. Sibutramine also causes a
September 2002
dose-related increase in blood pressure and heart rate that
usually occurs in the first few weeks of treatment and
lasts as long as the drug is taken. A dose of 10 to 15
mg/day causes an average increase in systolic and diastolic blood pressure of 2 to 4 mm Hg and an increase in
heart rate of 4 to 6 beats per minute.396,401 However,
some patients experience much larger increases in blood
pressure or heart rate and require dose reduction or
discontinuation of therapy.404 The risk of adverse effects
on blood pressure are no greater in patients with controlled hypertension than in those who do not have
hypertension.401,418 The use of sibutramine is contraindicated in patients with poorly controlled hypertension.
Orlistat. Many of the orlistat clinical trials included treatment arms that provided low doses of orlistat
(30 and 60 mg 3 times daily) that were not effective and
are not currently available. Therefore, only the data
evaluating the standard dose of 120 mg 3 times daily
will be reviewed here. Seven prospective randomized
controlled trials of ⱖ1 year duration have been published
that evaluated the efficacy of orlistat therapy in initiating
and maintaining weight loss (Table 9).290,397,420 – 424
Compared with placebo, the efficacy of orlistat in achieving weight loss was consistent across studies. At 1 year,
approximately one third more patients treated with orlistat lost 5% or more of their initial body weight than
did those treated with placebo; approximately twice as
many patients treated with orlistat lost 10% or more of
their initial body weight as those in the placebo group.
Subjects who were enrolled in a trial conducted within a
primary care practice setting, which did not include
behavior therapy or interaction with a dietitian,422 did
not do as well as those enrolled in trials that provided
formal behavior modification and dietary counseling.290,397,420 Successful weight loss also was more difficult to achieve in patients with type 2 diabetes mellitus423 and in those with risk factors for CHD, including
hypertension and dyslipidemia.424
Several randomized controlled studies have evaluated
the effectiveness of orlistat in maintaining initial weight
loss. Four trials represent a second year extension of
1-year studies reviewed previously.397,402,420,422 In these
trials, energy intake was liberalized during the second
year with a goal of preventing weight regain, rather than
inducing further weight loss. Approximately half of the
subjects who initially were randomized completed the
entire 2 years. In all trials, weight regain occurred in
both placebo- and orlistat-treated groups after year 1,
but the total percent weight loss at the end of year 2 was
greater with orlistat than with placebo therapy. Weight
loss at 2 years was better when dietary counseling and
AMERICAN GASTROENTEROLOGICAL ASSOCIATION
909
behavior modification therapy were incorporated into the
treatment program than when the trial was conducted in
a primary care setting without formal behavioral or
dietary counseling. At 2 years, 34% of subjects given
behavior modification therapy plus orlistat lost 10% or
more of their initial weight,420 compared with 19% of
subjects given orlistat within a primary care setting.422
One trial evaluated the efficacy of orlistat therapy in
weight maintenance after initial weight loss was induced
by diet alone.425 A total of 729 obese subjects who lost
ⱖ8% of body weight after completing a 6-month weight
loss program were prescribed a weight-maintaining diet
and randomized to receive orlistat or placebo therapy
for 12 months. Compared with placebo, subjects given
orlistat had slightly greater total weight loss (8.2%
vs. 6.4% of initial body weight) and less weight regain (32% vs. 56% of lost weight). Furthermore, 48%
of patients treated with orlistat compared with 30% of
patients treated with placebo maintained at least 75%
of their lost weight; 24% of patients treated with orlistat
compared with 16% of patients treated with placebo did
not regain any weight or continued to lose weight.
Comparing the results from this latter study425 with data
obtained from a similar study that evaluated the effectiveness of sibutramine in weight maintenance419 suggests that orlistat is not as effective as sibutramine in
maintaining diet-induced weight loss (Figure 10). How-
Figure 10. Weight maintenance during 1 year of treatment with either
sibutramine or orlistat after subjects achieved successful initial
weight loss by diet alone. The amount of initial weight loss, achieved
by 4 weeks of treatment with a very low-calorie diet in the sibutramine
trial and after 6 months of treatment with a low-calorie diet in the
orlistat trial, is represented by the black bars. Total weight loss 1 year
after initial intensive diet therapy was stopped for those randomized
to receive placebo (white bars) or drug (striped bars) during the
maintenance period. (Data for the sibutramine trial were obtained
from Apfelbaum et al.419 and data for the orlistat trial were obtained
from Hill et al.425)
910
AMERICAN GASTROENTEROLOGICAL ASSOCIATION
ever, differences in dietary instructions make it difficult
to compare data reliably between studies, and further
evaluation of each medication given as part of a single
prospective randomized trial is warranted.
Data from several randomized orlistat clinical trials
suggest that orlistat may have a beneficial effect on serum
cholesterol concentration that is independent of weight
loss alone. Subjects administered orlistat had a greater
reduction in serum LDL-cholesterol concentrations than
those given placebo, even after adjusting for percent
weight loss.397,420 The mechanism responsible for this
additional lipid-lowering effect may be related to orlistat’s effect on dietary cholesterol absorption. By using
cholesterol tracer methods, it was reported that orlistat
ingestion with a meal decreased dietary cholesterol absorption by 25%.426
It has been hypothesized that, in addition to blocking
the absorption of fat, orlistat helps patients lose weight
by encouraging dietary fat restriction to avoid the gastrointestinal side effects of fat malabsorption. In fact, it
has been suggested that orlistat may be a behavior modification tool by acting as an “Antabuse” for fat. However, data from 2 prospective trials revealed that, compared with placebo, orlistat therapy did not cause a
further decrease in fat intake in subjects prescribed a
low-calorie, low-fat diet (⬃60 g of fat per day).425,427
Moreover, the energy lost from malabsorbed fat was
greater than expected based on the observed weight loss,
suggesting that orlistat’s effect on body weight can be
accounted for by fat malabsorption alone, rather than by
modification of fat intake.
Orlistat side effects. The most common side effects experienced with orlistat therapy are related to
orlistat’s action on gastrointestinal lipases. In 1- and
2-year trials,290,397,420 – 424 approximately 70% to 80% of
subjects treated with orlistat experienced one or more
gastrointestinal events (listed in Table 10) compared
with approximately 50% to 60% of those treated with
placebo. Gastrointestinal events usually occurred early
(within the first 4 weeks), were of mild or moderate
intensity, were usually limited to 1 or 2 episodes, and
resolved despite continued orlistat treatment. Approximately 4% of subjects treated with orlistat and 1% of
subjects treated with placebo withdrew from the studies
because of gastrointestinal complaints. The gastrointestinal side effect profile of one illustrative study is shown
in Table 10.397 Subjects who completed year 1 on placebo therapy: and switched from placebo to orlistat during year 2 experienced the same number of gastrointestinal side effects during year 2 as those initially treated
with orlistat experienced during year 1. Subjects who
GASTROENTEROLOGY Vol. 123, No. 3
were given orlistat during both years 1 and 2 had the
same number of gastrointestinal side effects in year 2 as
those treated with placebo had in year 1. Many of the
gastrointestinal side effects of orlistat can be prevented
by concomitant therapy with a gel-forming fiber (psyllium mucilloid).428
Long-term orlistat treatment can affect the homeostasis of certain fat-soluble vitamins. Acute absorption studies conducted in normal volunteers showed that orlistat
ingestion inhibited the absorption of ␤-carotene429 and
vitamin E,430 but not vitamin A.430 Assessment of serum
concentrations of fat-soluble vitamins and ␤-carotene
during 1- and 2-year orlistat clinical trials showed that
mean serum concentrations remained within the normal
range, although subjects were not allowed vitamin supplementation. Vitamin concentrations, usually vitamins
D, E, and ␤-carotene, decreased below normal limits in
approximately 5% more orlistat- than placebo-treated
subjects. These abnormalities resolved rapidly with vitamin supplementation.397,290,420 – 423 Therefore, it is recommended that all patients who are treated with orlistat
be given a daily multivitamin supplement that is taken
at a time when orlistat is not being ingested.
Orlistat can have medically significant effects on the
absorption of lipophilic medications if both drugs are
taken simultaneously. Several cases have been reported of
subtherapeutic plasma cyclosporin levels in organ transplant recipients after they began orlisat therapy for obesity.431– 433 Therefore, orlistat should not be taken for at
least 2 hours before or after the ingestion of lipophilic
drugs, and plasma drug concentrations should be followed to ensure appropriate dosing if possible. The results of pharmacokinetic studies suggest that orlistat
does not affect the absorption of selected drugs with a
narrow therapeutic index (warfarin, digoxin, phenytoin)
and selected drugs that are likely to be taken concomi-
Table 10. Gastrointestinal Side Effects of Orlistat Therapy
Year 1
Fatty/oily stool
Increased defecation
Oily spotting
Soft stool
Liquid stools
Abdominal pain
Fecal urgency
Flatulence
Flatus with discharge
Fecal incontinence
Oily evacuation
Year 2
Placebo
Orlistat
Placebo
Orlistat
5
7
1
9
10
9
3
3
0
0
1
31
20
18
15
13
7
10
7
7
7
6
1
2
1
2
5
7
2
2
0
0
0
8
2
6
6
8
7
3
3
1
2
5
Data from Sjöström L, et al.397
September 2002
tantly with orlistat (glyburide, oral contraceptives, furosemide, captopril, nifedipine, atenolol, and alcohol).434
There is a theoretical concern that long-term orlistat
therapy may increase the risk of specific gastrointestinal
diseases, such as gallstones and colon cancer. Orlistat
could increase gallstone formation because inhibition of
fat digestion prevents the release of fatty acids into the
intestinal lumen, which is needed to stimulate cholecystokinin secretion and gallbladder contraction.413 However, orlistat administered with meals of varying fat
content does not reduce gallbladder motility,435 and
there is no evidence of increased gallstone formation in
the thousands of subjects who have completed 1- and 2year orlistat clinical trials.307,402,420 – 425 The increased
delivery of fat to the colon has raised a concern of
increased colon cancer risk. However, orlistat administration in obese volunteers does not increase colonocyte
proliferation,436 and there is no evidence of an increased
incidence of colon cancer in subjects who took orlistat in
clinical trials. Nonetheless, studies of longer duration
would be useful to confirm these data.
Surgical Therapy
Indications for Surgery
Gastrointestinal surgery is the most effective approach for achieving weight loss in severely obese patients. In 1991, a NIH Consensus Conference established
guidelines for the surgical treatment of obesity.437 The
panel concluded that patients with class III obesity
(BMI ⱖ40 kg/m2) or those with class II obesity (BMI
35.0 –39.9 kg/m2) and one or more severe obesity-related
medical complications (e.g., hypertension, type 2 diabetes mellitus, heart failure, or sleep apnea) are eligible for
surgery. Moreover, potential candidates should be patients who are unable to lose weight or maintain weight
loss with conventional therapy, have acceptable operative
risks, and are able to comply with long-term treatment
and follow-up. Active substance abuse is an absolute
contraindication.
Types of Surgical Procedures
Surgical therapy for obesity can be classified into
2 general categories: (1) procedures that primarily cause
gastric restriction and (2) procedures that primarily cause
maldigestion and malabsorption (Table 11). This section
will focus particularly on the risks and benefits of the
gastric bypass procedure (GBP) because it accounts for
more than 90% of the bariatric surgery procedures currently being performed in the United States.
GBP. The GBP, also known as a Roux-en-Y gastric bypass, involves construction of a small (10 to 30
AMERICAN GASTROENTEROLOGICAL ASSOCIATION
911
mL) proximal gastric pouch by stapling across the stomach or complete transection from the rest of the stomach
(Figure 11A). The pouch empties into a segment of
jejunum that is brought up to the gastric pouch as a
Roux-en-Y limb. The length of the Roux-en-Y limb is
variable, depending on the size of the patient. For example, a 45- to 100-cm limb (proximal or short-limb GBP)
often is used in patients with a BMI ⬍50 kg/m2, whereas
a limb of 150 cm or more (distal or long-limb GBP)
usually is reserved for patients with a BMI ⱖ50 kg/m2.
In one study, conducted in patients with BMI ⱖ50
kg/m2, a 150-cm limb achieved greater weight loss than
a 75-cm limb, without increasing the risk of nutrient
deficiencies.438 Although the gastric bypass is considered
a restrictive procedure, it causes some malabsorption as a
consequence of the bypassed stomach, duodenum, and
upper jejunum. No randomized clinical trials have evaluated the most effective pouch or stomal size for optimal
weight loss. However, many bariatric surgeons believe
that the gastric pouch should be as small as possible (just
large enough to construct a gastrojejunostomy) and that
the stoma should be about 1 cm in diameter.
Complications specifically related to the GBP procedure include early complications of hemorrhage, gastrointestinal leak leading to peritonitis, splenic injury,
wound infection, and late complications of stomal stenosis, marginal ulcers, staple line disruption, dilation of
the bypassed stomach, internal hernias, specific nutrient
deficiencies, and dumping syndrome.
Stomal stenosis occurs in 5% to 15% of patients and is
manifested as nausea and vomiting after eating.439 Although stomal stenosis after gastric bypass usually can be
treated by endoscopic balloon dilatation, it is occasionally necessary to surgically revise the gastrojejunal anastomosis. If not treated, stomal stenosis can cause serious
nutrient deficiencies, including thiamine deficiency with
Wernicke-Korsikoff encephalopathy and profound peripheral neuropathy.440,441 Therefore, upper gastrointestinal endoscopy should be performed at the first sign of
Table 11. Surgical Procedures for Weight Loss
Classification
Procedure
Primarily gastric restriction
Gastric bypass (Roux-en-Y
gastric bypass)
Gastroplasty (VBG)
Gastric banding
Biliopancreatic diversion
Biliopancreatic diversion with
duodenal switch
Distal gastric bypass
JIB (small bowel bypass)a
Primarily maldigestion/
malabsorption
aThis
procedure is no longer recommended because of unacceptable
side effects.
912
AMERICAN GASTROENTEROLOGICAL ASSOCIATION
Figure 11. Gastric restrictive surgical procedures: (A) GBP and (B)
VBG.
recurrent nausea and vomiting, before patients develop
dehydration or electrolyte and vitamin deficiencies.
Marginal ulcers develop in 5% to 15% of patients and
almost always occur on the jejunal side of the gastrojejunostomy.439 Staple line disruption increases the risk of
this complication because of persistent bathing of the
anastomosis with acid.110 Marginal ulcers usually respond to acid-suppression therapy; however, approximately 10% of patients with ulcers (1% of all patients)
will need surgery to resect the ulcer.
On rare occasions, ulceration and friability at the
anastomosis cause gastrointestinal bleeding, which usually resolves with conservative therapy. Upper gastrointestinal bleeding that cannot be detected by endoscopy
usually is caused by a duodenal ulcer that cannot be
visualized because of anatomical reconstruction of the
intestine. Therefore, empiric acid-reduction therapy is
indicated in the absence of endoscopic evidence of a
marginal ulcer. Assessment of Helicobacter pylori status, by
using a serum or breath test, is useful to identify patients
who may benefit from H. pylori eradication.
Staple line disruption often is heralded by a marked
increase in the ability to eat large volumes of food or by
the presence of a marginal ulcer that is refractory to
acid-suppression therapy. Surgical revision, which can be
technically difficult because of adhesions from the previous surgery, is required.110
Dilation of the bypassed stomach can occur as an acute
postoperative problem and usually presents as hiccups
and complaints of bloating. The diagnosis can be confirmed with a plain, upright abdominal film showing a
dilated, air-filled distal stomach. This complication usually can be treated by percutaneous fine-needle aspiration. However, if dilatation recurs, an endoscopic or
surgically placed gastrostomy tube may be necessary to
prevent gastric necrosis or disruption of the gastrojejunostomy.111
GASTROENTEROLOGY Vol. 123, No. 3
Internal hernias usually occur at 3 sites: (1) where the
Roux limb passes through the mesocolon, (2) at the
jejunojejunostomy, and (3) between the jejunal and colonic mesenteries. It is critical to recognize symptoms of
an internal hernia (i.e., cramping and periumbilical pain,
with or without nausea and vomiting) because emergency surgery is needed to prevent intestinal necrosis
from a closed-limb obstruction.111 The decision to operate is based on clinical suspicion because an upper gastrointestinal radiographic (UGI) film may not detect the
problem.
Certain nutrient deficiencies, particularly iron, calcium,
folic acid, and vitamin B12, are common after gastric
bypass surgery because of impaired absorption and decreased intake.442– 445 Premenopausal women are particularly susceptible to the development of iron-deficiency
anemia because of blood loss during menses, in addition
to surgery-induced iron malabsorption caused by both
anacidity and duodenal bypass. Osteoporosis can occur
because of calcium malabsorption. Serum calcium concentration remains normal because of calcium mobilization from bone but alkaline phosphatase and other markers of bone turnover often are increased. More than 50%
of patients become vitamin B12 deficient if they do not
take oral supplementation. Vitamin B12 deficiency probably is caused by inadequate acidity needed to release
vitamin B12 from food; the Schilling test is generally
normal. Folate deficiency is rare and probably occurs
because of decreased intake. Many nutrient deficiencies
can be prevented by appropriate mineral and vitamin
supplementation. All gastric surgery patients should
take supplemental calcium and a multivitamin containing folate and vitamin B12 daily. Vitamin B12 also can be
provided by oral, intramuscular, or intranasal routes.
Menstruating women should also take supplemental iron
with meals. Some patients also may require additional
magnesium or zinc.
Dumping syndrome often occurs after gastric bypass
surgery because ingested food traverses directly from the
gastric pouch into the jejunum. Patients who eat a large
volume of food or energy-dense liquids that have high
sugar content or high osmolality often complain of
dumping symptoms, including nausea, abdominal pain,
flushing, tachycardia, and diarrhea. This “complication”
is probably beneficial because it prevents excessive ingestion of carbohydrate-dense foods.
Gastroplasty. Gastroplasty (Figure 11B), also
known as gastric stapling, can be performed in 2 ways. The
first procedure, known as VBG, involves stapling the
front to the back of the stomach below the gastroesophageal junction and 1 cm from the lesser curvature with a
September 2002
surgical stapling device that cuts out a hole. A vertical
staple line is then made from the opening to the left side
of the gastroesophageal junction, and the outlet stoma is
restricted with a 1-cm diameter polypropylene band.446
The second procedure, known as silastic ring gastroplasty,
involves constructing a vertical staple line along the
lesser curvature to the left side of the gastroesophageal
junction, with a notched stapling device that leaves an
opening (stoma) distally. The stoma is then restricted
with a 1-cm diameter silastic ring.447
Complications specifically related to gastroplasty include stomal stenosis, staple line disruption, erosion of
the band, and increased gastroesophageal reflux. Stomal
stenosis prevents adequate nutrient intake and causes
dehydration and vitamin deficiencies. Although an attempt to dilate stenoses by endoscopic balloon dilatation
should be made, this approach usually is unsuccessful
because of the fixed band and generally is best managed
by surgical conversion to a gastric bypass.439 Staple line
disruption, which can occur in up to 35% of patients,
leads to rapid weight regain.448 In some patients, gastroesophageal reflux can be a severe and serious complication, requiring conversion to a gastric bypass.110,111 In
contrast to the GBP, gastroplasty does not cause dumping syndrome or iron or vitamin B12 deficiency.
Comparison between gastric bypass and gastroplasty on weight loss. Four prospective, randomized tri-
als448 – 451 that compared VBG with GBP consistently
found that weight loss was greater with the latter procedure. In addition, many,452– 454 but not all,455 retrospective studies found that weight loss with gastric
bypass was superior to weight loss with gastroplasty. In
the first randomized trial to evaluate the 2 procedures,
average loss of excess weight at 1 year after surgery was
42% with VBG and 68% after the GBP; weight loss
remained significantly different between groups during a
3-year follow-up period449 (Figure 12). Moreover, independent long-term evaluations of each procedure suggest
better results with the GBP than VBG. Average weight
loss after the GBP was maintained up to 14 years after
surgery,279 whereas a recent study reported poor weight
loss at 10 or more years after VBG.456 The mechanism
responsible for the difference in weight loss between the
2 procedures is not known, but may be related to increased susceptibility to dumping and lactose intolerance
associated with GBP. These symptoms may cause a decrease in the intake of foods with high sugar content and
high-calorie milk products, such as ice cream and milkshakes.449,457 In fact, patients who eat a large portion of
their calories as sweets (“sweet eaters”) lose substantially
more weight with the GBP than with the VBG.449
AMERICAN GASTROENTEROLOGICAL ASSOCIATION
913
Figure 12. Percentage of excess weight (⫾ SD) lost over 36 months
after the GBP and VBG. (Adapted with permission from Sugerman et
al.449)
However, even when “sweet eaters” are excluded, patients who undergo gastric bypass still experience more
weight loss than those who have VBG.458 Therefore,
gastric bypass is currently considered the gold standard
for obesity surgery in many centers.
Gastric banding. The laparoscopically inserted
adjustable silicone gastric band (LASGB) is currently the
most popular bariatric surgical procedure being performed in Europe.459 The LASGB recently was approved
for clinical use in the United States by the Food and
Drug Administration (USFDA). The band is placed
around the upper stomach, just distal to the gastroesophageal junction. A balloon in the band is connected to a
subcutaneously implanted port that can be accessed percutaneously to inflate or deflate the band, and thereby
change the size of the band circumference. Some studies
found that weight loss with this device was equivalent to
a VBG,459 whereas other investigators have found the
average loss with LASBD was much less than that
achieved by GBP.460
Complications of the LASGB are less common and less
severe than those that occur with either the GBP or
gastroplasty. These complications include band slippage,
esophageal dilatation, erosion of the band into the stomach, band or port infections, and balloon or system leaks
that lead to inadequate weight loss.461,462 Band slippage
occurs when the posterior stomach wall herniates
through the band, which can cause gastric obstruction
and require surgical revision. Band placement at the
gastroesophageal junction can cause esophageal dilatation and dysphagia.461 Loosening the band usually decreases the dilatation but sometimes band removal is
required; in some patients, the band erodes into the
stomach, which also requires surgical removal.462
Jejunoileal bypass (JIB). The JIB, first reported
in 1969, was designed to bypass most of the small
914
AMERICAN GASTROENTEROLOGICAL ASSOCIATION
Figure 13. Biliopancreatic diversion with duodenal switch. (Data from
Marceau et al.474)
intestine and induce weight loss by malabsorption of
ingested calories. The original procedure was constructed
with 8 inches of jejunum connected end-to-side to the
ileum 4 inches from the ileocecal valve.463 To prevent
reflux of food into the bypassed intestine and increase
weight loss, the operation was then changed to an endto-end jejunoileostomy with the bypassed small bowel
drained into the colon.464 The JIB procedures were associated with many serious complications caused by protein-calorie malnutrition, bacterial overgrowth and
translocation, and excess oxalate absorption (e.g., cirrhosis, interstitial nephritis, migratory arthritis, bypass
enteritis, erythema nodosum, oxalate urolithiasis, hypocalcemia, and electrolyte imbalances).465– 469 These
operations are no longer performed because of the unacceptable rate of serious side effects. Patients who experience one or more of the JIB complications that are
related to bacterial overgrowth (e.g., migratory arthritis,
elevated liver enzymes, bleeding from inflammation in
the bypassed intestine) can be treated successfully with
oral metronidazole.468 – 469 Patients refractory to antibiotic treatment or who suffer other serious consequences
of the procedure, such as progressive liver disease, require
surgical revision. If a JIB is surgically corrected, a GBP
should be performed at the time of surgery unless the
patient has severe cirrhosis with portal hypertension
because reversal of the JIB is associated with regain of all
lost weight and recurrence of previous obesity-related
diseases.470
Biliopancreatic diversion. Biliopancreatic diversion, also known as partial biliopancreatic bypass, is designed to induce gastric restriction, maldigestion, and
malabsorption. In this operation, a partial gastrectomy is
performed with creation of a 500-mL capacity proximal
gastric pouch for patients with a BMI ⬍50 kg/m2 or a
200-mL capacity pouch for those with a BMI ⱖ50
kg/m2. The small intestine is transected 250 cm from the
GASTROENTEROLOGY Vol. 123, No. 3
ileocecal valve, and the distal end is anastomosed to the
gastric pouch. The proximal limb is then connected to
the ileum, 50 cm from the ileocecal valve. These anastomoses create a 200-cm “alimentary tract,” a variable
length (300- to 500-cm) “biliary tract,” and a 50-cm
“common tract” where digestion and absorption of ingested food occur. The biliopancreatic diversion causes a
greater amount of weight loss (⬃75% of excess weight)
than gastric restrictive procedures.
Biliopancreatic diversion causes more nutritional abnormalities (e.g., osteoporosis) and gastrointestinal complications (e.g., frequent, foul-smelling steatorrheic
stools) than gastric restrictive procedures because of malabsorption of protein, fat, fat-soluble vitamins, iron,
calcium, and vitamin B12.471– 474 The size of the gastric
pouch is inversely correlated with the risk of protein
deficiency, which can occur in 100% of patients when
the pouch is only 30 mL in size.472,474 In contrast to the
JIB, the bypassed intestine produced by this procedure
usually does not develop bacterial overgrowth because
the bypassed limb is “washed” with bile and pancreatic
juices. Consequently, biliopancreatic diversion rarely is
associated with liver damage; migratory arthritis and
renal disease have not been reported with the procedure.
However, after this procedure some patients may develop
fever and diarrhea that respond to metronidazole therapy,
suggesting the presence of bacterial overgrowth in the
biliopancreatic limb.472
Biliopancreatic diversion with duodenal switch.
This operation, also known as partial biliopancreatic bypass
with duodenal switch, is a modification of the biliopancreatic diversion procedure474 – 476 (Figure 13). The procedure involves removal of approximately 60% of the
greater curvature of the stomach (sleeve gastrectomy),
which causes gastric restriction but allows better preservation of gastric physiological function than a distal
gastrectomy. In addition, the proximal duodenum is
transected, the distal end of the duodenum is closed, and
the proximal duodenum is anastomosed to distal intestine, 250 cm proximal to the ileocecal valve. The proximal intestine is then connected to the ileum, 100 cm
from the ileocecal valve. This procedure causes greater
weight loss (⬃75% of excess weight) than a standard
gastric bypass.
Patients who have this procedure are able to eat normal volumes of food and do not develop dumping syndrome symptoms because of the regulation of gastric
emptying by an intact pyloric sphincter. The incidence
of protein deficiency is probably less common and gastrointestinal side effects are not as severe after biliopancreatic diversion with duodenal switch than after bilio-
September 2002
pancreatic diversion with distal gastric resection. In
addition, sparing the pylorus decreases the risk of marginal ulceration.
Laparoscopic obesity surgery. All obesity surgical procedures have been performed laparoscopically. The
laparoscopic approach is becoming more available because the number of centers performing the procedures is
increasing rapidly. The laparoscopic gastric bypass is
technically challenging with a steep learning curve. The
time needed to perform the procedure and the incidence
of complications decrease with increased experience. The
results from initial large series477,478 and a randomized
controlled trial479 demonstrate that weight loss after the
laparoscopic procedure is the same as that after the open
procedure.477– 479 The laparoscopic approach is associated
with decreased wound complications (infection and incisional hernia), decreased postoperative pain, less blood
loss, improved cosmesis, shorter hospital stay, and an
earlier return to a functional life. Late anastomotic strictures occur more frequently after laparoscopy than open
procedure but the rate of postoperative anastomotic leaks
and the costs are the same.479
Complications Associated With All Bariatric
Surgical Procedures
Perioperative mortality rate after open obesity surgical procedures reported in studies containing large
numbers of patients is usually ⬍1.5%.279,448,480 Approximately 75% of the deaths are caused by anastomotic leaks and peritonitis and 25% by pulmonary
embolism.
Anastomotic leak with peritonitis is a devastating complication that can be very difficult to diagnose because
patients rarely develop peritoneal signs despite the presence of peritonitis. Symptoms of a leak include left
shoulder pain, tenesmus and urinary urgency, increased
back pain, and a feeling of “impending doom.” Signs
include fever and tachycardia.111,481 The diagnosis requires a high degree of suspicion and can sometimes be
confirmed with a water-soluble contrast UGI series.
However, if the patient has had a gastric bypass, the leak
may be from the bypassed stomach and will not be seen
by a UGI series. If a leak is suspected, the safest course
of action is to re-explore the patient. The leak rate after
open gastric bypass is approximately 2.5% in most series,
and the mortality risk from this complication is approximately 0.3%.279,482 Patients who have sleep apnea or
obesity hypoventilation syndrome have a higher mortality risk.299
The risk of pulmonary embolism after surgery is increased
in extremely obese patients. Although many surgeons
use intermittent venous compression boots, as well as
AMERICAN GASTROENTEROLOGICAL ASSOCIATION
915
standard or low-molecular-weight heparin to reduce this
risk, no studies have carefully evaluated the risk-reduction of any prophylactic approach. In one series, the risk
of a fatal pulmonary embolism was 0.2% and increased
to 4% in patients with severe venous stasis disease.483
The presence of severe pulmonary hypertension in association with obesity hypoventilation can increase the risk
of fatal pulmonary embolism,304 which raises the consideration of prophylactic Greenfield inferior vena cava filter
placement in these patients.
Gallstones will form in approximately one third of
patients within 6 months after a gastric restrictive procedure; the incidence may be higher in patients who have
had a malabsorptive procedure. As noted previously, the
incidence of gallstone formation is markedly decreased
with ursodeoxycholic acid therapy.122 Although some
surgeons perform cholecystectomy routinely at the time
of the bariatric surgical procedure, most only perform
cholecystectomy in patients who have gallstones already
present at the time of the procedure. The risk of incisional
hernia is markedly increased after any abdominal surgery
in a severely obese patient compared with a lean patient.484 In fact, the risk of incisional hernia after bariatric surgery in extremely obese patients is greater than
the risk in patients who undergo a colectomy and ileoanal pouch procedure for ulcerative colitis, despite the
latter having a much larger incision and compromised
wound healing because of prednisone therapy. Overall,
postoperative incisional hernia occurs in 15% to 25% of
patients but the risk is higher in patients with a prior
incisional herniorrhaphy or patients with diabetes, obesity hypoventilation syndrome, or sleep apnea. Wound
infections occur more commonly after any abdominal operation in severely obese than in lean patients, presumably because of the increased amount of deep subcutaneous fat.
Inadequate Weight Loss or Weight Regain
After Surgery
On average, at 1 to 2 years after GBP, patients
lose two thirds of their excess weight (one-third of their
total weight). At 5 and 10 years after surgery, the average
loss of excess weight is 60% and 50%, respectively.279,482
Better long-term weight loss of ⬃75% of excess weight
is observed after the partial biliopancreatic bypass or
duodenal switch procedures.471,474 – 476 Approximately
15% of patients will fail to lose more than 40% of their
excess weight (10% to 15% of total weight) after a
GBP,279,482 and an even greater percentage of patients
fail to lose this amount of weight after gastroplasty
procedures.456 The primary cause of failed weight loss
after gastric bypass is the frequent ingestion of high-fat
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AMERICAN GASTROENTEROLOGICAL ASSOCIATION
snacks (e.g., potato or corn chips), fried foods (e.g.,
french-fried potatoes), and high-calorie soft foods and
liquids (sodas, lemonade, milkshakes, cookies, and ice
cream). In patients who have undergone either a stapled
gastroplasty or gastric bypass, increased food intake may
be related to staple line disruption, particularly if the
patient is able to eat much larger quantities of food at a
time. An UGI series is needed to diagnose this complication, which requires surgical revision. Revisional procedures for bariatric procedures carry a higher risk of
complications, including anastomotic leak.485 Dilation of
the gastrojejunal stoma can occur, but it probably does
not impede weight loss, and surgical revision does not
lead to greater weight reduction.486 Patients who have
not responded to a standard gastric bypass and have
severe obesity-related diseases such as drug-resistant hypertension, obesity hypoventilation, or diabetes are potential candidates for conversion to a malabsorptive procedure. Although converting a standard gastric bypass to
a malabsorptive distal gastric bypass is effective for
weight loss, this approach increases the risk of development of protein-calorie malnutrition, steatorrhea with
foul-smelling stools, and fat-soluble vitamin deficiencies.472
Medical Management of Bariatric Surgery
Patients
Careful evaluation and management of patients
before and after surgery are important to exclude inappropriate surgical candidates, provide counseling
regarding postoperative lifestyle, diet, and weight loss
expectations, and decrease the risk of postoperative complications. The initial evaluation should include a careful
medical assessment with particular attention to concomitant medical illnesses that increase the risk of surgery. A
psychological assessment can help identify patients who
might experience an adverse outcome because of psychiatric problems, such as severe depression, suicidal ideation, substance abuse, or inadequately treated psychosis.
Dietary counseling is needed before and after surgery to
help patients adjust to the marked changes required of
their dietary habits. Dietary intake after surgery usually
progresses from liquids (days 2 to 3), to pureed foods
(days 4 to 30), to soft foods (days 31 to 45), to small, 2to 3-oz portions of regular food (after day 45). When
dietary intake is stable, patients should consume 6 to 8
cups of fluids per day, ingest high-protein foods, and take
vitamin and mineral supplements. After the first postoperative year, a medical examination should be performed annually and should include blood tests to evaluate hemoglobin, plasma mineral concentrations
(particularly iron, magnesium, and calcium), and se-
GASTROENTEROLOGY Vol. 123, No. 3
lected vitamin concentrations (folate and vitamin B12).
Fat-soluble vitamins A, D, and E should also be monitored in patients who have had malabsorptive procedures, such as the long-limb gastric bypass or biliopancreatic diversion.
Intragastric Balloon Therapy
The observation that gastric bezoars cause weight
loss487 led to the concept of using intragastric balloons as
a method of obesity therapy. In 1985, the Garren Edwards Gastric Bubble became the first endoscopically
placed intragastric balloon approved by the USFDA.
However, an unacceptable incidence of gastric erosions
and ulcers, balloon deflation, and small bowel obstruction caused by migration of deflated balloons led to the
removal of the Garren Edwards Gastric Bubble and later
the Wilson-Cook balloon from the marketplace. Nonetheless, continued efforts to develop a safe and effective
intragastric balloon have led to a new generation of
balloons with a low potential for gastric irritation and
deflation. In addition, these balloons have a larger capacity (400 to 800 mL) than earlier models to enhance
weight loss, and the volume in selected balloons can be
endoscopically adjusted to accommodate for patient size,
gastrointestinal symptoms, and rate of weight loss.
Currently, intragastric balloons are not available for
use in the United States but are being used for weight
loss therapy in selected patients in other countries, primarily in Europe. The complication rates observed with
these balloons are much lower than those observed with
the Garren Edwards Gastric Bubble. The composite of
results from several studies showed that mucosal damage
occurred in ⬃4% and balloon deflation in ⬃7% of
subjects.488 It usually is recommended that the balloon
be removed or replaced within 3 to 6 months of insertion
to reduce the risk of complications. Longer placement
periods might be safe with appropriate monitoring by
x-ray or ultrasound to ensure that adequate balloon inflation has been maintained. Recently, colonic impaction
caused by migration of a deflated balloon was reported in
one patient 9 months after balloon placement.489
Data from published randomized controlled trials of
currently available devices, conducted in extremely obese
subjects for up to 8 months, have not demonstrated
consistent benefits of intragastric balloon therapy on
weight loss.490 – 495 Most,490 – 494 but not all495 trials, revealed that weight loss in subjects who had intragastric
balloon placement (in conjunction with diet therapy) was
similar to that in subjects who had sham endoscopy and
diet therapy. In all negative trials, patients randomized
to sham balloon placement and diet therapy achieved con-
September 2002
siderable weight loss. Therefore, the successful weight-management program in these studies may have made it
difficult for balloon therapy to provide additional benefits. For example, in one study of extremely obese patients who had a BMI ⬎50 kg/m2 and weighed ⬎150
kg, the control group lost ⬃50 kg at 8 months of
treatment. Additional studies, of much longer duration
and in a more typical clinical practice setting, are still
needed to determine the long-term efficacy and safety of
intragastric balloons.
Patient Expectations
There is a considerable discrepancy between a
realistic weight loss goal and the patient’s expected
weight loss goal. Obese persons who seek nonsurgical
therapy for obesity typically want to lose 2 to 3 times
more weight than usually is achieved with current behavioral and pharmacologic treatments. In a recent
study, obese women who were beginning a weight loss
program indicated they wanted to lose 38% of their body
weight but would be happy with a loss of 31%, satisfied
with a loss of 25%, and disappointed with a loss of 17%
of initial body weight.496 After 48 weeks of intensive diet
and exercise therapy, these women lost an average of
16.4% of their initial weight. In another study, patients
who were about to begin treatment with sibutramine and
group lifestyle modification expected to lose twice as
much weight (25% of initial weight) as they actually lost
(11.5% of initial weight) at the end of 1 year.404 Patients
who seek bariatric surgery also often have unrealistically
high weight loss expectations.497
Many obese patients will accept extraordinary risks
and hardships to lose weight. Rand and Macgregor498
found that patients who had maintained a weight loss of
ⱖ100 pounds for 3 or more years after gastric surgery
would rather lose their hearing, become blind, or lose a
leg than regain their lost weight. We found that 1 in 4
obese patients enrolled in our own weight-management
program were willing to accept an 8% annual mortality
risk to lose 12% of their body weight and a 21%
one-time chance of immediate death to obtain their
self-described desired weight (B. Weiss, R. Nease, and
S. Klein, unpublished observations, 2000). Despite this
exceptional desire by many obese patients to lose weight,
most are unable to make the necessary long-term changes
in daily lifestyle needed for successful weight loss.
These findings underscore the importance of carefully
reviewing patients’ treatment expectations and setting
realistic goals. It is important to clarify what patients can
and cannot expect with regard to changes in weight,
health complications, body image, and social function-
AMERICAN GASTROENTEROLOGICAL ASSOCIATION
917
ing. Moreover, obese patients who are not candidates for
bariatric surgery must ultimately be convinced that losing 10% of initial weight is a success, even if they remain
overweight or obese after treatment. They should know
at the outset that the principal goal of treatment, like
that of other medical therapies, is to improve health and
well-being, not appearance.
Treatment Guidelines for
Overweight and Obesity
The clinical approach to overweight and obese
patients involves many of the same principles used in the
management of other chronic diseases, which also rarely
are cured but can be controlled with proper treatment.
Obesity requires constant vigilance, and its clinical
course is often characterized by periods of weight stability and relapse. Unwavering support from physicians and
other caregivers, within the context of a long-term treatment program, will enhance the chance for long-term
weight management.
Appropriate management requires identifying patients who need treatment, developing a realistic treatment plan, and implementing a defined treatment strategy that can be modified as needed during long-term
surveillance. A Practical Guide to the management of
overweight and obesity, published as a monograph in
October 2000, was developed by the North American
Association for the Study of Obesity in conjunction with
the NIH.416 The Practical Guide was based on earlier
clinical guidelines developed by an expert panel convened by the National Heart, Lung and Blood Institute
(NHLBI).4 In this section, guidelines for obesity therapy
adapted from the Practical Guide with modifications
based on recent additional information are presented.
Assessment
A careful medical evaluation is needed to identify
patients who either have, or are at risk for, obesityrelated medical complications. This assessment should
include a determination of BMI and other obesity-related
risk factors, including the amount of weight gained since
young adulthood and the patient’s level of cardiovascular
fitness. Although the amount of weight gain that is
associated with increased risk of obesity-related diseases
has been documented,16 –21 the amount and type of regular physical activity needed to decrease the risk of
obesity-related disease are not known. However, in view
of the preponderance of evidence that physical activity
and aerobic fitness are inversely related to cardiovascular
disease,499 it seems prudent to use the recommendations
made by the Centers for Disease Control and Prevention,
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AMERICAN GASTROENTEROLOGICAL ASSOCIATION
the American College of Sports Medicine, and the American Heart Association regarding physical activity as
criteria for CHD risk.468,500 Based on these recommendations, overweight or obese persons who do not engage
in moderate physical activity (e.g., walking) for at least
30 minutes per day, 5 days per week, are at increased risk
for CHD.
The Practical Guide also recommends that waist circumference be determined because a “large” waist circumference, defined by the NIH guidelines as ⬎102 cm
(40 inches) in men and ⬎88 cm (35 inches) in women,
is an independent risk factor for a cluster of medical
abnormalities, including the components of the metabolic
syndrome and cardiovascular disease.4 However, recent
data obtained from more than 9000 participants in
NHANES III question the clinical utility of measuring
waist circumference.501 More than 99% of men and 98%
of women in the NHANES III sample would have received the same treatment recommendations proposed by
the NHLBI Expert Panel and the Practical Guide without
an assessment of waist circumference. It is possible that
lower waist circumference cutoff values could be more
effective in identifying overweight patients who are at
increased risk for obesity-related metabolic complications and, therefore, might benefit from more aggressive
obesity therapy. However, this issue requires further
study.
A history, physical examination, and laboratory tests
also should be performed to identify the presence of
CHD, other atherosclerotic processes, additional risk fac-
GASTROENTEROLOGY Vol. 123, No. 3
tors for CHD, and other obesity-related diseases that may
benefit from weight loss (Table 12). In addition, the
medical evaluation should be used to identify obesityrelated diseases (see Table 4) that may not necessarily
benefit from weight loss, but that require medical treatment.
Treatment
The goal of weight-loss therapy is to improve or
eliminate obesity-related comorbidities or decrease the
risk for future obesity-related medical complications.
The indications for weight loss therapy proposed by the
Practical Guide and the NHLBI Expert Panel focus on the
prevention and treatment of CHD. The composite of
body weight classification (based on BMI), current cardiovascular illnesses, and risk factors for future CHD
(identified by the medical examination) helps determine
the need for and aggressiveness of obesity therapy. However, in addition to CHD and its risk factors, obesity
causes other serious medical illnesses (Table 4). Therefore, it is reasonable to include other obesity-related
illnesses that improve with weight loss as additional
indicators for treatment (Table 12).
Table 13 provides general guidelines for selecting
among treatment options that are available for weight
management. An effective treatment plan must consider
patients’ willingness to undergo therapy, their ability to
comply with specific treatment approaches, access to
skilled caregivers, and financial considerations. Weight
loss therapy is not recommended for patients with a BMI
Table 12. Risk Factors and Diseases That May Influence Obesity Therapy
1. Presence of cardiovascular disease
a. CHD (history of myocardial infarction, angina, coronary artery surgery, or coronary artery procedures)
b. Other atherosclerotic processes (peripheral arterial disease, aortic aneurysm, and carotid artery disease)
2. Presence of obesity-related diseases that increase CHD risk
a. Hypertension (systolic blood pressure ⱖ140 mm Hg, or diastolic blood pressure ⱖ90 mm Hg, or taking antihypertensive medications)
b. High serum LDL cholesterol (ⱖ160 mg/dL)
c. Low serum HDL cholesterol (⬍35 mg/dl)
d. Impaired fasting plasma glucose (110–125 mg/dL) or type 2 diabetes mellitus
3. Presence of additional risk factors for CHD
a. Family history of premature CHD (myocardial infarction or sudden death at or before 55 years of age in father or other male firstdegree relative, or myocardial infarction or sudden death at or before 65 years of age in mother or other first-degree female relative)
b. Age ⱖ45 years for men and ⱖ55 years for women (or postmenopausal)
4. History of lifestyle-associated risk factors
a. Cigarette smoking
b. Weight gain of 5 kg or more since the age of 18–20 years
c. Sedentary lifestyle (⬍30 min/day of moderate activity 5 days/week)
5. Presence of additional obesity-related diseases that may benefit from weight loss
a. NAFLD (steatosis and steatohepatitis)
b. Polycystic ovary syndrome
c. Venous disease (venous stasis, deep vein thrombosis)
d. Pulmonary disease (abnormal pulmonary function, obstructive sleep apnea, obesity hypoventilation syndrome)
e. Musculoskeletal abnormalities (osteoarthritis, low back pain)
f. Gynecologic abnormalities (abnormal menses, infertility)
g. Urinary stress incontinence
September 2002
AMERICAN GASTROENTEROLOGICAL ASSOCIATION
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Table 13. Suggested Weight Loss Treatment Options Based on BMI and Risk Factors
BMI category (kg/m2)
Treatment
25.0–26.9
27.0–29.9
30.0–34.9
35.0–39.9
ⱖ40.0
Diet, physical activity, and
behavior therapy
Pharmacotherapya
Surgeryb
With risk factor
With risk factor
Yes
Yes
Yes
With obesity-related disease
Yes
Yes
With obesity-related disease
Yes
Yes
aPharmacotherapy should be considered only in patients who are not able to achieve adequate weight loss by available conventional therapy
(diet, physical activity, and behavior therapy) and who do not have any absolute contraindications for drug therapy.
bBariatric surgery should be considered only in patients who are unable to lose weight with available conventional therapy and do not have any
absolute contraindications for surgery.
⬍25 kg/m2; however, providing recommendations for a
healthy lifestyle, including dietary and physical activity
modification, is reasonable for lean persons who have, or
are at increased risk for, metabolic and cardiovascular
diseases.
Characteristics of Successful Weight
Maintenance
Certain characteristics are common among patients who have achieved successful long-term weight
loss without bariatric surgery. Persons who maintain
their weight loss report that they: (1) monitor their food
intake, physical activity, and body weight regularly; (2)
consume a diet that is low in calories (1300 to 1400
kcal/day) and fat (⬃25% kcal as fat); (3) eat breakfast
daily; and (4) engage in high levels of regular physical
activity (expending ⬃2800 kcal/week equivalent to
walking ⬃4 miles per day).335,335a In addition, successful
weight loss often was preceded by a medical or emotional
triggering event and was followed by improvements in
energy level, physical mobility, mood, self-confidence,
and physical health.
Future Research Directions
Future research in obesity should be directed toward the following: (1) developing more effective prevention strategies, (2) improving obesity treatment, and
(3) improving our understanding of the pathophysiological effects of excess adiposity. Prevention and treatment
efforts in children and adolescents are particularly important because successful weight management in these
age groups will help prevent obesity in adulthood.
The current obesity epidemic can be attributed, in
large part, to a “modern” environment that implicitly
discourages physical activity and explicitly encourages
the consumption of supersized portions of high-fat, highsugar foods. Therefore, to be successful, prevention efforts will need to target the “modern” environment.
Traditional approaches that have emphasized education
and individual responsibility have not been, and are
unlikely to be, effective. Many people know what they
must do to prevent or eliminate obesity but simply are
unable to implement the lifestyle changes needed to lose
weight permanently or prevent weight gain. Obesity
prevention strategies should involve public and private
sector partnerships between community leaders, school
administrators, employers, health care providers, and
governmental agencies. Such an approach must be sensitive to issues of individual rights and freedom of choice.
Nonetheless, it is likely that successful prevention will
require bold public policy initiatives to enhance safe and
easy access for physical activity and to facilitate lowcalorie food choices. Reasonable concepts should be
tested carefully for feasibility and effectiveness in clinical
trials that involve varied ethnic and socioeconomic groups.
Additional research efforts are needed to improve treatment for persons who are already obese. These studies
should further define the roles of macronutrient composition, meal replacement therapy, specific exercise/activity
programs, and innovative technological approaches (e.g.,
the Internet) in achieving and maintaining long-term
weight loss. The most exciting new developments in
obesity therapy probably will be derived from research
that improves our understanding of the molecular mechanisms responsible for regulating energy balance. This
information may lead to the development of new and
effective pharmacologic agents that decrease energy intake and/or increase energy expenditure. The use of individual medications, combinations of medications, and
medications plus other treatment tools will need to be
studied in long-term (⬃5 year) clinical trials. Finally, the
long-term effectiveness and safety of new surgical approaches (e.g., gastric pacing and laparoscopic techniques) and efforts to decrease postoperative complications need to be studied in randomized controlled trials.
The mechanisms responsible for the link between
excess adiposity and many obesity-related diseases are not
clear. Therefore, additional research is needed to identify
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AMERICAN GASTROENTEROLOGICAL ASSOCIATION
the cellular and physiological factors that are responsible
for organ and tissue damage related to excess total body
fat and specific fat distribution patterns. The recent
mapping of the human genome provides exciting new
opportunities for understanding the pathogenesis and
pathophysiology of obesity, which could lead to improved therapeutic approaches for both obesity and obesity-related medical complications.
GASTROENTEROLOGY Vol. 123, No. 3
12.
13.
14.
SAMUEL KLEIN
Department of Internal Medicine and Center for
Human Nutrition
Washington University School of Medicine
St. Louis, Missouri
15.
THOMAS WADDEN
Department of Psychiatry
University of Pennsylvania
Philadelphia, Pennsylvania
17.
HARVEY J. SUGERMAN
Department of Surgery
Medical College of Virginia of Virginia
Commonwealth University
Richmond, Virginia
19.
16.
18.
20.
21.
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Address requests for reprints to: Chair, Clinical Practice Committee,
AGA National Office, c/o Membership Department, 7910 Woodmont
Avenue, 7th Floor, Bethesda, Maryland 20814. fax: (301) 654-5920.
Supported by National Institutes of Health grants DK 37948, DK
56341, DK12614, and RR-00036.
Dr. Klein has received honoraria for speaking engagements on
obesity from Roche Laboratories and R. W. Johnson; is a member of
the Obesity and Diabetes Educational Council, which is funded by an
unrestricted educational grant provided by Roche Laboratories; and
has received research support for clinical studies from Roche Laboratories, R.W. Johnson, DMV International, Regeneron Pharmaceuticals,
Novartis Nutrition, and GlaxoSmithKline. These funds were used for
participating in multicenter clinical research trials and for investigatorinitiated research in obesity.
Dr. Wadden serves on the speakers’ bureau for Abbott Laboratories
and Roche Laboratories, which manufacture the weight-loss medications sibutramine and orlistat, respectively. He has received research
support from Schering-Plough, GlaxoSmithKline, and Abbott Laboratories.