I Introduction
Several
epidemiological studies have considered the impact of increasing body
weight, body mass index (BMI) and other anthropometric measurements
on the risk of chronic disease (1, 2), including coronary heart
disease (CHD), type 2 diabetes mellitus (DM), hypertension, stroke,
and cancers of the breast, endometrium, prostate and colon (3).
Though previous observational studies have used BMI as a measure of
general or overall adiposity, growing evidence suggests that a
central (abdominal) fat distribution pattern, as reflected by a
higher waist circumference or waist-to-hip ratio (WHR) may be more
related to risk than elevated body weight, particularly among older
adults (2, 4-6). For example, individuals with a higher
proportion of abdominal fat have a greater risk of developing
coronary heart disease (5, 6), type 2 diabetes mellitus (DM) (7-9)
and cardiovascular disease (CVD) related
morbidity and mortality (2, 4, 10, 11)
than those with a lower proportion.
Using waist circumference data from the National Health and Nutrition
Examination Survey (NHANES), Li and colleagues (12)
have found that the prevalence of
abdominal obesity has increased continuously over the past 15 years.
Abdominal obesity, as reflected by WHR, presumably contributes to the
risk of CVD through its mediated effects on other cardiovascular risk
factors, such as hypertension, dyslipidemia, and insulin-resistance
glucose intolerance (2, 13). The metabolic syndrome, a
condition characterized by central obesity, disturbed glucose and
insulin metabolism, mild dyslipidemia and hypertension, clusters
these obesity-related risk factor (14). Recent estimates
indicate that the prevalence of metabolic syndrome is increasing in
the US (15), with approximately 40% over the age of 60 years
affected. In addition, the prevalence of metabolic syndrome is also
increasing among adolescents (12). The metabolic syndrome has been
linked with increased risk of both type 2 DM and CVD (16-18)
Some
researchers have suggested that waist circumference is a better
predictor of obesity-related health risk than BMI (19, 20).
Others, however, are reluctant to replace BMI with an abdominal
adiposity measurement, such as waist circumference or WHR, as the
only clinical
measurement to indicate health risks associated
with overweight and obesity (21,
22), because both general and abdominal adiposity are independent
risk factors for certain diseases. Nevertheless, both arise as
a consequence of weight gain, and conversely both respond to weight
loss. Therefore, it is important to elucidate the mechanisms
and independent roles of body fat distribution on the etiology of
chronic diseases.
Weight
fluctuations as a result of repeated failures maintain weight loss
have also been associated with increased risk of developing chronic
diseases (23, 24) and
excess mortality (23, 25). Although earlier studies suggested that
weight fluctuation is associated with increased mortality, those
findings may reflect inadequate or incomplete measures, or failure to
incorporate variables that accurately characterize weight changes.
Difficulties in determining whether the changes are weight gain,
weight loss or weight flux with limited time points, together with
the need to distinguish between intentional and unintentional weight
loss, increase the complexity of examining weight flux in relation to
disease risk. In the Chicago Western Electric Company Study, in
which multiple weight measures clearly discerned between weight gain,
weight loss, and weight variability, weight flux did not appear to be
a predictor of increased mortality (26). Evidence from the
British Regional Heart Study suggested that increased mortality
associated with weight loss and weight fluctuation was due to the
effects of preexisting disease and smoking rather than the effects of
weight loss and weight flux per se (27).
While
excess body weight is clearly associated with increased risk of
mortality, the optimal body weight to minimize mortality risk is
equivocal. Whereas morbid obesity has been clearly linked
to higher mortality rates (28), the relation between low to moderate
body weight and all-cause mortality is less clear (29).
Several observational studies have reported a U- or J-shaped
association between overweight and mortality, (11, 30-32), yet other
studies have found a gradual increase in mortality with increasing
weight, particularly among non-smokers (33-35).
Furthermore, some have questioned whether the recommended BMI
cut-off points for determining overweight and obesity are applicable
for identifying health risks associated with adiposity regardless of
ethnicity status (36-38). In a study of 527,265 men and women,
although an increased risk of death was observed among those
individuals in the highest and lowest BMI category, upon further
restriction to healthy, non-smokers, the risk of death was associated
with overweight and obesity status only (11). Thus, although
the curve’s shape relationship between BMI and mortality is
debatable, observational studies have consistently reported that
adults with a BMI greater than 30 kg/m2
have higher mortality rates (11, 28, 33, 39).
Clearly,
the health consequences and compromised quality of life associated
with obesity provide major incentives to abate the continuing obesity
epidemic. However, despite recognition of these effects, the
epidemic of overweight and obesity has not reversed and in minority
groups continues to escalate (40-42). Levels are also high in much of
the developed (43) and
developing world (44). According to data from the continuing
NHANES, 71% of men and 62% of women are overweight or obese, with
prevalence varying among the three major racial/ethnic groups in the
U.S (42). As prevalence increases, the rising economic costs of
obesity continue to be a major health burden for national health
economies (45). Recent estimates indicate that obesity accounts
for 7% of direct health care costs in the US, with diseases such as
CHD, type 2 DM and osteoarthritis accounting for 48 billion dollars
of total obesity-attributable medical costs annually (46).
Furthermore, compared with adults of normal weight, adults with
BMI >40 had an approximately 64% higher risk of diabetes, a 54%
higher risk of high blood pressure, a 9% higher risk for high
cholesterol, a 17% for higher risk for asthma, a 34% higher risk for
arthritis, and a 32% higher risk for generally fair or poor health
(47). Fortunately, mounting evidence indicates that many
of the health risks associated with obesity can be reversed with
weight loss (48). In the Framingham Heart Study, weight loss
was associated with improvements in blood pressure and cholesterol
levels (49). Other studies have confirmed that weight loss can
improve metabolic risk factors among overweight persons with
hypertension, dyslipidemia, insulin resistance and type 2 DM
(50-55). The prevalence of obesity has also increased in
children in several countries including the US, China, Brazil and
Russia (56). Obesity in children is associated with an
increased risk for many obesity-related diseases including diabetes
and CVD risk factors (57-59), left ventricular hypertrophy related to
hypertension (60), and metabolic syndrome (61)
although the utility of a diagnosis of
metabolic syndrome has been challenged (57, 62).
Because
body fat distribution is linked to obesity and is of particular
importance in the etiology of certain chronic diseases, this chapter
will provide the reader with an overview of the epidemiological
evidence linking both overweight and body fat distribution to the
risk of several chronic diseases in adults. This chapter will
complement Chapter 1, in which the indicators of obesity are covered
in detail, and Chapter 13, which provides a full discussion of the
pathophysiology of obesity-related health conditions.
II
Cardiovascular disease risk factors and cardiovascular disease
1.
Cardiovascular Risk Factors
a.
Hypertension
Both
cross-sectional (63-65) and
prospective studies (66, 67) have
linked obesity to hypertension.
Recent
estimates suggest that, after adjustment for other risk factors (such
as age, BMI, degree of weight cycling, physical activity, smoking,
and alcohol consumption), each kilogram increase in body weight
increases the risk for developing hypertension by 4.4% (68). In
a nationally representative sample (69), the prevalence of elevated
blood pressure dramatically increased with increasing weight,
particularly among individuals aged less than 55 years.
Similarly,
among postmenopausal women, the risk of developing high blood
pressure doubled with either a high BMI or high WHR (2),
suggesting
that both general and abdominal obesity are important risk factors.
These
observational studies are corroborated by clinical intervention
trials, which have consistently found that weight loss effectively
lowers blood pressure (70, 71). In
the Framingham study (72), a weight loss of 6.8 kg or more led to a
28% reduction in the risk of hypertension (RR = 0.72; 95% CI: 0.49 –
1.05) for middle-aged adults and a 37% reduction for older adults (RR
= 0.63; 95% CI: 0.42 – 0.95). The study also reported that
sustained weight loss over 4 years resulted in a 22% reduction in
hypertension risk among middle-aged adults (RR = 0.78; 95% CI: 0.60 –
1.03) and a 26% reduction (RR = 0.74; 95% CI: 0.56 – 0.97) in
older adults. Overall, it appears that the prevalence of
hypertension increases even with relatively small increases in body
weight (68, 73).
Furthermore,
in hypertensive subjects, overweight is associated with
cardiovascular abnormalities such as increased progression of left
ventricular hypertrophy (74)(75). Another study showed that in
addition to a reduction in blood pressure, weight loss and exercise
may induce favorable changes in left ventricular structure related to
cardiovascular events (76). Given that high blood pressure
represents one of the most common modifiable risk factors for CVD
risk, obesity-related hypertension could be reversed with weight
loss, thus reducing CVD risk at the population level.
b.
Dyslipidemia
Dyslipidemia
is characterized by elevated total cholesterol and triglyceride
levels, normal to elevated LDL cholesterol, reduced HDL cholesterol
and raised low-density lipoprotein apo B.
Several
observational studies (64, 65, 77-81)
have
observed associations between body weight and plasma lipoproteins.
In
the Framingham Heart Study, weight gain over a 26-year follow-up
period was associated with adverse lipid profiles and weight loss was
associated in improvements in cholesterol (82). Other
studies have found that changes in body weight are associated with
changes in lipid concentrations (55, 83, 84). Findings
from the Framingham Offspring Cohort provide further evidence that
BMI is significantly and linearly associated with total cholesterol,
LDL cholesterol and triglyceride concentrations, and is inversely
associated with HDL cholesterol in nonsmoking men and women (65);
the
latter observation is consistent with other studies (64, 85).
In
contrast to weight gain, weight loss and exercise may result in lower
LDL cholesterol and triglyceride levels, decreases in the total
cholesterol to HDL cholesterol ratio, and increases in HDL
cholesterol levels (86, 87). Furthermore, cohort (88),
case-control (89) and
intervention studies (90) have
found that a high LDL to HDL cholesterol ratio, as well as high
triglyceride to HDL cholesterol ratio and small LDL-size in the
presence of hypertriglyceridemia, are associated with the highest CVD
risk (91). This
unfavorable lipid profile is commonly found in obese adults (92).
c.
Hyperinsulinemia
Insulin
resistance is a condition characterized by increased insulin
production and impaired glucose tolerance, and is probably the most
frequent abnormality seen in association with central or visceral
abdominal adiposity (93, 94). Insulin
resistance may underlie a number of other metabolic disorders
including hypertension, hyperglycemia and impaired glucose tolerance,
hypertriglyceridemia, and hypercholesterolemia (14). This
clustering of risk factors has been termed insulin
resistance syndrome,
syndrome X
or
metabolic syndrome
and is
discussed in detail in Chapter 9.
It
is worth noting, however, that although each individual risk factor
conveys only a small increase in CVD risk, the overall impact on CVD
risk is substantial due to the coincidence of these risk factors
(95).
Increasing
central obesity has been independently associated with insulin
resistance, hyperinsulinemia and a progressive increase in insulin
and glucose concentration in response to an oral glucose tolerance
test (96). Some
have proposed that central obesity promotes insulin resistance
through increased levels of free fatty acids which causes the muscle
tissue to utilize more fat fuel thereby impairing the
insulin-mediated uptake and utilization of glucose. The
accumulation of free fatty acids is also associated with oxidative
stress and the impairment of microvascular functions (97-100).
Central
obesity may also induce insulin resistance through release of
inflammatory cytokines such as IL-6, which in turn impair insulin
action in diverse tissues (101, 102).
Alternatively,
insulin resistance in obesity may be attributed to both a decrease in
insulin receptors and intracellular post-receptor defects in insulin
action (103, 104). Furthermore, abnormal secretion of several
adipocyte hormones such as leptin (105, 106), adiponectin (106)
and
ghrelin (107), which are primarily regulated by insulin-induced
changes of adipocyte metabolism, may be potential targets for
managing obesity and insulin resistance.
Insulin
resistance has been associated with weight gain in some (108, 109),
but not all observational studies (110, 111). In young
adults, weight gain over a 7-year follow-up period was positively
associated with concentrations of fasting glucose and insulin
(112).. Wilson and colleagues found that weight gain over 16
years predicted development of features of the insulin resistance
syndrome (113). However,
it has been proposed that insulin resistance is an adaptation for
maintaining stable weight, such that the oxidation of fat tends to be
favored over its storage and over the oxidation of glucose (114).
Data
from several observational studies of different ethnic groups support
this hypothesis that higher fasting insulin is associated with lower
weight gain (110, 111, 115). Interestingly, conflicting data
have been found in children indicating that hyperinsulinemia and
insulin resistance may favor weight gain (116).
In
women, the body fat distribution pattern often changes with
progression through menopause (117). Greater
increases in waist circumferences and WHR in postmenopausal women
compared to women who remain premenopausal may contribute to increase
risk of chronic diseases, such as type 2 DM.
Van
Pelt et al. (118) in
a large cohort of healthy postmenopausal women found that waist
circumference was significantly associated with hyperinsulinemia and
elevated triglyceride concentrations among women with a normal range
of BMI (24-28 kg/m2).
Furthermore,
the combination of insulin resistance and the accumulation of
visceral adipose tissue in the abdominal compartment contribute to
the most unfavorable metabolic risk profiles in post-menopausal women
(119).
2.
Cardiovascular Disease
a.
Obesity and CHD risk
Several
studies have found a strong association between obesity and CHD risk
(120-122). Again,
obesity is strongly linked to several cardiovascular risk factors
including diabetes, hypertension, and dyslipidemia.
These
risk factors could represent intermediate steps in the causal pathway
between obesity and CHD risk; therefore, considerable debate exists
over whether adjustment for these risk factors is desirable or
represents “overcontrol”
and
introduces, rather than controls, bias (123). Most
observational studies that did not
control
for risk factors reported associations between BMI and CHD (10, 120,
121, 124). In
the Nurses’ Health
Study, the relative risk (RR) of CHD was over three times higher
among women with BMI’s of
>29
kg/m2
compared to those with BMI’s
of less
than 21 kg/m2,
after adjustment for age, smoking, menopausal status, hormonal use
and parental history of CHD (122). After
excluding women with self-reported diabetes or hypertension, the
magnitude of the risk of CHD between the same extreme categories of
BMI was attenuated, but remained moderate (RR 3.6 versus 2.6).
A
recent study from an English cohort found that almost 60% of the
10-year coronary risk in this population was attributable to BMI >25
kg/m2
(125).
Although this study did not control for hypertension and
dyslipidemia, they observed that systolic blood pressure and total
cholesterol increased sharply with increasing BMI among men with WHR
less than 0.95 and was high at all levels of BMI among men with WHR
exceeding
0.95.
Similarly, observation studies that controlled
for one or more coronary risk factors in the analyses found that
while BMI remained independently associated with CHD risk,
associations tended to be attenuated (5, 39, 120, 126). In
1998, the American Heart Association (AHA) concluded that obesity was
a independent coronary heart disease risk factor (127).
Other
studies support the AHA’s statement that obesity increases the
risk of CHD events (128-131), although other CHD risk factors such as
hypertension, dyslipidemia and diabetes might explain some, but not
all, of the association between obesity and CHD (131).
Furthermore, a large international, case-control study reported that
in all regions of the world, for both men and women, abdominal
obesity increased the population attributable risk of myocardial
infarction, (one of the most common CHD events) to 80.2%, from 75.8%
attributed from hypertension, diabetes and dyslipidemia (132).
At the population level, obesity appears to be a well-defined and
consistent hazard for CHD.
In
contrast to the findings of studies of young and middle-aged adults
(39, 126, 133), a
direct relation between BMI and CHD risk has not consistently been
found among older age groups (>60 years) (5, 134, 135). Rimm
and colleagues (5) found
that among men <65 years of age, the risk of CHD increased
threefold (RR 3.44; 1.67-7.09) for men with a BMI greater than 33
compared with lean men (BMI <23.0), yet in older men the risk was
substantially lower (1.26; 95% CI 0.37-4.30) between the same extreme
categories. Other
prospective studies have reported a lack of association between BMI
and coronary disease among older populations
(134)(135).
These age-related differences in obesity and CHD risk may reflect
early onset coronary artery disease incidence among overweight
persons, changes in the relative proportion of fat free and lean body
mass with age (136) or
weight loss due to a sub-clinical disease (137).
b.
Body fat distribution, weight change and CHD risk
A
growing body of evidence indicates that abdominal visceral adiposity
may have more significant health consequences than BMI on CVD
incidence and mortality (2, 4-6, 138).
While
the exact mechanism is unknown, it is postulated that excess
abdominal adiposity may be more predictive of CVD risk than BMI
because of its stronger association with other cardiovascular risk
factors (139).
Furthermore,
a positive association between abdominal visceral fat and
pathological changes of the coronary arteries indicate that the
process of coronary atherosclerosis would have occurred even before
individuals are clinically diagnosed for CHD (140).
Rexrode and colleagues (6)
found
that after adjustment for BMI and other cardiac risk factors, women
with a WHR greater than 0.88 were more than 3 times as likely to
develop CHD during an 8-year follow-up compared to women with a WHR
of less than 0.72. In
this same cohort, waist circumference was also significantly
associated with increased risk of CHD, even after controlling for BMI
(6). Another
large population-based cohort found that WHR was positively
associated with the incidence of CHD in both younger and older women
while BMI was related to CHD only among women aged 55 years or under
(141). Several other longitudinal studies also observed
associations between abdominal obesity and CHD among middle-aged and
older women (128, 142). Using a similar methodology in a large
prospective study of men, Rimm et al (5)
found
that in men <65 years of age, BMI was strong predictor of CHD,
whereas after age 65, WHR was a better predictor of risk among men.
In
contrast, another prospective study from a different cohort found
that abdominal obesity was an independent risk factor for CHD in
middle-aged men (18). Interestingly, Rexrode et al (143)
found a
modest relationship between abdominal obesity, as measured by either
WHR or waist circumference, and risk of CHD both in middle-aged and
older men. These associations were reduced substantially when BMI was
accounted for. In a case-control study, Sonmez et al (144)
did not
observe WHR to be statistically different between the age groups of
male-CHD cases. As also shown in the WHO MONICA study (145)
the
sensitivity and specificity of detecting abdominal adiposity may be
population-specific. Furthermore, measures of abdominal obesity such
as waist circumference may complement BMI assessment in
cardiovascular risk assessment (146, 147). Specific thresholds
of waist circumference within BMI categories may be required to
identify those at increased risk of CHD, however.
Weight
gain, even in modest amounts (5-7.9 kg), has been associated with
increased risk of CVD (122, 126). In
fact, Willet and colleagues estimated that for every kilogram
increase in body weight, the risk of developing CHD among women
increased 3.1% (122).
Furthermore,
fluctuations in body weight have also been associated with CHD risk
(23,
148). In
the Framingham Heart Study, individuals who fluctuated in body
weight, as reflected in large relative standard error of the
regression coefficient, experienced more CHD events that individuals
who maintained a normal weight
(23).
In the Nurses Health Study, weight gain from age 18 to age 55
was significantly associated with future risk of CHD after adjustment
for BMI (149).
Rapid
weight gain in childhood has been shown to be associated with CHD
later in life. Individuals with a low weight at birth who gain weight
rapidly after 1 year of age are at an elevated risk for developing
CHD in later in life (150)(151).
3.
Obesity, body fat distribution and risk of stroke
In
contrast to the epidemiological studies linking obesity and CHD risk,
fewer studies have examined the association between obesity and
stroke incidence and mortality
(152-157).
Current
evidence for an association between general obesity and risk of
stroke is conflicting, with some studies suggesting that a higher BMI
is associated with stroke incidence (126, 154, 156, 157), while
others report no association (4,
152, 155, 158, 159). In
the Nurses’ Health
Study, the risk of ischemic stroke was directly related to BMI, with
women whose BMI was greater than 32 kg/m2 at 2.4 (RR 2.4; 95% CI
1.6-3.5) greater risk of ischemic stoke compared to those with a BMI
of <21 kg/m2
(156).
In
contrast, the risk of hemorrhagic stroke was inversely related to
obesity in the same cohort, with highest risk among the leanest
subjects. Using
a similar methodology in a large prospective study of men, Walker et
al. (155), reported no association between BMI and incidence of total
stroke, of which approximately 70% were ischemic strokes.
Interestingly,
recent studies demonstrate a significant association between BMI and
risk of stroke among men (160-162), especially for total stroke and
ischemic stroke.
It
has been suggested that abdominal obesity, as measured by WHR, is a
better predictor of stroke than BMI. Men with a WHR of >0.98
were twice as likely to suffer a stroke compared to men with a WHR
<0.89
(155).
In women, these associations seem less consistent (128, 163).
Significant
associations between WHR and stroke incidence have been reported in
other observational studies as well
(4,
153, 163-165).
III
Diabetes Mellitus
1.
Obesity and type II diabetes mellitus
Approximately
200 million people in the world have diabetes, and the number is
predicted to rise to over 300 million by the year 2025 (166).
In the US, an estimated 64%-74% incident cases of type 2 DM could be
prevented if BMI’s were below 25 kg/m2
(167). The prevalence of diabetes was stable across all BMI
groups over the past 40 years, whereas other co-morbid conditions
related to obesity, such as high blood pressure and dyslipidemia,
have declined over time within BMI groups (168). Both
cross-sectional (69)(169-171) and
prospective cohort studies (172-174)
have consistently found strong positive
associations between BMI and risk for type II diabetes mellitus.
In the Nurses’ Health Study the relative risk of diabetes for
women with a BMI of 25.0-29.9 kg/m2
increased 8-fold, for those with BMI 30-34.9 kg/m2
increased 20-fold, and for those with a BMI of 35 kg/m2
or greater increased 39-fold, compared with those with a BMI <
23.0 kg/m2(175).
The steep, linear risk gradient gives larger studies, in which there
are adequate data to have a very lean referent, highly elevated
relative risks. Other studies have found that the risk for developing
diabetes increases exponentially in both men and women with
increasing BMI (2, 69, 173, 176). For example, a recent
prospective study in men shows an increased incidence risk of type 2
diabetes across BMI quintiles, with the most dramatic increase from
the 4th
(BMI 25.4-27.2) to the 5th
quintile (27.2-54.2) (177).
2.
Body fat distribution, weight change and type II diabetes
In
addition to BMI, other independent determinants that predict the risk
of type II diabetes include WHR (2, 8, 171, 178), waist circumference
(173, 178-180), weight gain or loss, and duration of obesity (49,
173, 181). Folsom and colleagues (2)
found that women with a low BMI had
markedly elevated diabetes risk if they also had a high WHR.
In contrast, Chan et al (173) found
that WHR was only weakly associated with risk of type 2 DM in men
after controlling for BMI, yet waist circumference remained an
independent predictor of type 2 DM risk. Likewise, a 13-year
follow-up study indicated that waist circumference was better than
WHR in predicting type 2 DM in men (177). Lean and colleagues
(179) found
that among men and women with a large waist circumference (≥102
and ≥88 respectively) the risk of developing type 2 DM increased
4.5 and 3.8 fold, respectively. Because greater waist
circumference accounts for greater abdominal fat, especially visceral
fat (146), it is more closely related to insulin sensitivity than the
subcutaneous fat (182); this might explain the consistent association
between waist circumference and type 2 DM.
Prospective
studies have shown that weight gain, even modest weight gain,
increases the risk of developing type 2 diabetes (17, 172, 173, 176,
181, 183). Recent estimates suggest that for every kilogram of
increase in body weight the risk for developing diabetes increases
5.4% (176). Wannamethee and colleagues (181)
prospectively examined the relation
between weight change and the incidence of type 2 diabetes in a
cohort of middle-aged British men over a 12-year follow-up period.
After adjustment for age, initial BMI, smoking, physical activity,
high blood pressure and recall of CHD, the risk of developing type 2
diabetes increased 1.6-fold among those who gained substantial weight
(>10%) compared to men who maintained stable weight. A
steady increase in type 2 diabetes risk has also been observed among
men and women who gained weight after adolescence (172, 173).
Conversely, weight loss has been associated with reduction in the
incidence of type 2 diabetes. Weight management through
lifestyle modification has been recommended for the prevention and
management of type 2 DM (184). A structured and intensive
lifestyle program involving
participant education, individualized counseling,
reduced dietary fat and energy
intake, regular physical activity,
and frequent participant contact
are necessary to produce long-term
weight loss of as much as 5–7%
of starting weight (185). The use of weight loss medications
and bariatric surgery may be useful in the treatment of overweight
persons with type 2 diabetes (186), but such medical intervention is
recommended only in conjunction with lifestyle strategies for
severely obese patients or in the presence of obesity-related
co-morbidities (185).
Several
intervention studies have found that weight loss is associated with a
reduced risk for diabetes among those at high risk of developing the
disease (i.e. severely obese, with impaired glucose tolerance (IGT)
or with a family history of diabetes) (187-189). One intervention
study found that weight loss plus exercise reduced the risk of
developing type 2 diabetes by 50% in individuals with impaired
glucose tolerance (189).
Wing et al. (188) found
that a modest weight loss of 4.5 kg over 2 years, as a consequence of
a lifestyle intervention including diet and/or exercise, reduced the
risk of developing type 2 diabetes by 30% relative to no weight
loss. Furthermore, the
positive effect of weight loss in reducing the risk of diabetes may
be modified by other risk factors. For example, a large
randomized controlled trial in men found that the weight loss
intervention reduced diabetes incidence among non-smokers, but not
among smokers (190). The benefits of weight loss and risk of
type 2 diabetes have been also been reported in population-based
settings (172, 181). Long-term maintenance of weight loss is
more important than initial weight loss. Klein et al (184)
reviewed some strategies that were
associated with successful long-term weight loss, such as eating a
low calorie, low fat diet, reducing portion sizes and snacking, daily
breakfast consumption, participating in regular physical activity,
and frequently monitoring body weight.
IV
Cancer
In
contrast to cardiovascular disease and diabetes, obesity receives
less attention as a risk factor for many cancers. In countries
where obesity is growing rapidly, such as the US, 3.2% of all new
cancers may be potentially attributable to obesity (191).
Elevated body weight has been linked with increased risk of some
cancers, including cancers of the colon, esophageal, prostate,
kidney, gallbladder and in women cancer of the breast and
reproductive system (192).
1.
Breast Cancer
A
complex relationship exists between obesity and breast cancer risk
(193).
While
some prospective studies have found that increased weight or BMI is
associated with increased breast cancer risk among postmenopausal
women (2, 194-199), others have found little or no association
(200-202).
Conversely,
among premenopausal women most cohort studies have found either no
association (198, 199, 202) or
an inverse association between BMI and breast cancer risk
(194,
197, 200, 201, 203, 204). One
explanation for this apparent interaction between obesity and
menopausal status on breast cancer risk is that obesity exerts
different effects on circulating endogenous sex steroid hormones
among postmenopausal women (205,
206).
Other
predictors, such as height (202, 203, 207, 208), body fat
distribution (2, 209-212), and weight change during adulthood (208,
211, 213, 214) have
also been linked to breast cancer.
In the
Nurses’ Health
Study (209), central adiposity determined by waist circumference and
WHR was associated with an increased risk of postmenopausal breast
cancer, with the greatest elevation in risk evident among
postmenopausal women who were not receiving hormone replacement
therapy.
2.
Endometrial Cancer
Obesity
is strongly related to endometrial cancer in both pre- and
postmenopausal women (192), with an estimated 34% to 56% of
endometrial cancer cases attributable to increased BMI
(213).
Several
cohort (194, 215-217) and
case control studies (218-224)
have
found a positive association between endometrial cancer and excess
weight, particularly among older women
(194,
218, 223). Although
less consistently than BMI, other measures of obesity such as waist
circumference (222, 225), waist-to-thigh ratio (220)
and
subscapular-to-tricep skinfold (a measure of central versus
peripheral obesity) (224) have
been positively associated with endometrial cancer, independent of
BMI. Despite
the fact that endometrial cancer is less common than breast cancer, a
greater number of endometrial cancer cases are attributable to
obesity.
3.
Colon Cancer
Colorectal
cancer is the fourth most common cancer in the world among both sexes
and the second in developed countries (226). Cohort studies
have consistently demonstrated a strong positive relationship between
BMI and risk of colon cancer in men (227-231)
with
weaker associations found in women
(231-234).
Murphy
et al.(231) examined
the association between BMI and colon cancer mortality over a 12-year
follow-up in 496,239 women and 379,167 men and found that the
relative risks of colon cancer mortality increased linearly across
all categories of BMI in men but not women.
These
authors suggest that the greater tendency for abdominal or central
adiposity in men may be one reason for the gender differences
observed in studies.
Alternatively,
the possible protective effect of estrogen may explain the observed
weaker associations between BMI and the risk of colon cancer among
women. A few observational studies found stronger positive
associations between obesity and colon cancer in premenopausal women,
but results have been inconsistent in postmenopausal women or those
taking hormone replacement therapy (235, 236)
Some
observational studies found that body fat distribution, as determined
by WHR or waist circumference, is an important independent risk
factor of colon cancer (2,
227, 233). In
the Health Professionals Follow-up Cohort Study, both waist
circumference and WHR were strong risk factors of
colon
cancer, independent of BMI (227).
In
this cohort, after accounting for BMI, relative risks of 3.41 (95% CI
1.52-7.66)
were seen for men with WHR ≥
0.99
compared to those with a WHR <0.90,
and relative risks of 2.6 (95%CI 1.33-4.96) were seen for men with a
waist
circumference ≥ 43
inches compared to men with a waist circumference <35 inches.
Furthermore, the effect of a higher BMI as well as greater waist
circumference may differ for cases of cancer occurring in the
proximal or distal colon (237).
4.
Kidney Cancer
Although
several risk factors of renal cell cancer have been identified,
including obesity, cigarette smoking, hypertension and certain
occupational exposures, the mechanisms by which these risk factors
contribute to the development of the cancer remain largely unknown
(192). However, based on evidence from case-control
studies, obesity represents one of the more consistently observed
risk factors for renal cell carcinoma (238-242)
with a more pronounced association found
among women (107, 242, 243). . However, a meta-analysis of 28
studies found that 27% of renal cell cancers cases among men and 29%
among women could be attributed to overweight and obesity (244).
Few
prospective studies have examined the importance of fat distribution
and how age-related changes in weight may influence risk of renal
cell carcinoma among older populations (13).
Prineas & Folsom (245) prospectively
examined the association among several risk factors for renal cell
carcinoma in 35,192 postmenopausal women over a 7-year follow-up
period. In this study, WHR, weight at age 18 and the degree of
weight gained between ages 18 and 50 years were independent
predictors of renal cell carcinoma. A prospective study
over 25 years of follow-up in Swedish men found that the risk of
renal cell cancer was almost doubled among men with a BMI ≥ 27.8
kg/m2 compared
to those with a BMI ≤ 21.8 kg/m2,
suggesting that even small excesses in body weight increase risk
among men (246). However, a study among Norwegian men and women
reported an increased risk of renal cell carcinoma in both sexes with
increasing BMI (247)..
Further
prospective cohort studies examining the association between body fat
distribution and renal cell carcinoma are warranted; however, current
evidence would suggest that a high BMI probably increases the risk of
renal cell carcinoma (192).
5.
Other Cancers
Variable
evidence exists for a role of overweight in relation to cancers at
other sites.
Several
studies report the incidence of gallbladder cancer to be positively
associated with body weight (246, 248), particularly among women
(246,
249). A
13-year prospective cohort study of 750,000 US men and women found
that gallbladder cancer mortality rates were significantly higher
among overweight women, but not overweight men
(248).
Based on the limited evidence, it would appear that gallbladder
cancer may be associated with a high BMI, particularly among women
(192).
With
respect to prostate cancer, some observational studies have suggested
that body weight is associated with an increase risk of prostate
cancer (248, 250-252); however the vast majority have found no
consistent association
(253-255).
Recent studies suggest that obesity may be associated with more
advanced forms of prostate cancer (256, 257). Interestingly,
prostate-specific antigen (PSA) levels, one of the methods to
diagnose prostate carcinoma, are inversely associated with BMI
(258). Furthermore, 15% of biopsy-detected prostate cancer is
in men with normal PSA levels (259). Misclassification of the
diagnosis of prostate cancer due to improper diagnostic methods may
be one of the possible explanations for the inconsistent association
between obesity and prostate cancer. Another
longitudinal study showed that although overweight people (BMI >25)
have lower PSA levels and a lower stage of disease at diagnosis, they
have a greater risk of being in a worse prognostic group then those
with normal BMI (260). Thus, further investigations are needed
to confirm whether the role of obesity is an important risk factor
for prostate cancer.
IV
Morbid conditions associated with obesity
Several
additional diseases and health conditions are associated with
overweight and obesity.
1.
Gallbladder disease
It
is somewhat ironic that obesity and weight loss among obese persons
are each independent risk factors for gallbladder disease (261). In a
systematic review of the effects of weight loss on gallstone
formation in obese patients, Everhart (261)found that 10-25% of
men and women may develop gallstones during the first months of a
highly calorie-restricted diet, with about one-third going on to
develop symptoms of gallbladder disease.
Most
gallstones in the US are thought to be cholesterol gallstones, and
their association with obesity is thought to be a consequence of
excessive hepatic secretion of cholesterol, resulting in bile that is
cholesterol-supersaturated (262). The sex-specific differences
for gallbladder disease are striking, with prevalence much higher in
women than men, and important differences existing across
racial/ethnic groups within sex (263). An analysis of
NHANESIII data (69) found prevalence ratios of 4 to 21 across obesity
classes of increasing severity for women under age the age of 55
years. Although women age 55 and over, as well as men (both older and
younger), experienced elevated risks with increasing degrees of
obesity, these associations were of more moderate magnitude. In
middle-aged men and women studied prospectively over a 10-year
period, risks of the development of gallstones across obesity classes
were similar for men and women, with relative risks of about 3 for
the most severe obesity class (1). In women,
obesity and adult weight gain after age 18 are each important
predictors of gallstones (264). Compared to women with BMI <
21 kg/m2, relative risks ranged from 2.8 (95% CI 1.8-4.3)
for BMI of 25 to 27 kg/m2 to 6.1 (95% CI 3.6, 10) for BMI
>36 kg/m2. Risk of gallstones for women who had major
weight gain (> 15kg) after the age of 18 of age was
three-fold higher compared to women who remained weight stable.
Overall, obesity has been consistently shown to be a powerful risk
factor for the development of gallbladder disease in women. Although
men have a lower prevalence of gallstones than women, a recent
prospective study in the US (265) found that abdominal obesity, as
reflected by waist circumference or waist-to-hip-ratio, is a strong
predictor of the incidence of gallstones in men independent of BMI.
This suggests that abdominal obesity may be a better predictor than
obesity of gallstone formation in men. Furthermore, the
presence of metabolic syndrome was associated with a more than 3-fold
increase in the risk of gallstone disease (OR = 3.2; 95% CI 1.7-6.0)
(266).
Sleep
apnea & respiratory problems
As
described in greater detail in Chapter 13, obese patients suffer from
a variety of respiratory complications such as obstructive sleep
apnea (OSA) (267, 268), obesity hypoventilation syndrome (269),
symptoms of dyspnea, and possibly increased risk of asthma (270,
271). One recent study found that over 50% of obese patients
with a mean BMI > 40 kg/m2
were affected by OSA (267), a higher estimate than had been
previously reported (268). A large population-based study reported
that for BMI > 28 kg/m2,
the prevalence of excessive daytime sleepiness, which is considered
to be a cardinal sign of sleep apnea, increased in an exponential
manner (268, 272). In a population-based prospective study of
602 Wisconsin employees, an increase of 1 SD in BMI was associated
with a 4-fold increase in risk of OSA (273). Further evidence
suggests central obesity and increased neck circumference are more
important risk factors for OSA (267, 274). Several dietary
intervention studies have found that weight loss has been associated
with improvements in sleep-disordered breathing (275-277). Given that
OSA is an important risk factor for hypertension (278), CVD (279),
stroke (280), glucose intolerance, and insulin resistance (281),
weight loss may simultaneously reduce sleep breathing disorders and
other morbid health conditions in obese patients.
The
findings of cross-sectional studies suggest that individuals with
asthma tend to weigh more (282, 283). In US adults, results
from the NHANES III (1988-1994) indicate that one in three persons
with asthma is obese, which is 44% higher than the prevalence of
obesity among persons without asthma (284). The directionality
of the relation is difficult to assess, given that obese patients may
gain weight as a result of reduced physical activity. In a
recent longitudinal analysis based on 89,061 women aged 27-44 years
from the Nurses’ Health Study, BMI and weight gain were both
significantly and prospectively associated with the development of
adult-onset asthma after controlling for other risk factors including
age, race, smoking, physical activity, energy intake, hysterectomy
status, birth weight and duration of breastfeeding (271).
In this study, nurses who gained more than 25 kg since the age
of 18 years had the highest RR for the development of asthma (4.7;
95%CI, 3.1-7.0) compared to those who remained weight stable.
Chen and colleagues (270) examined the relation between obesity and
asthma in 17,605 Canadians participating in the National Population
Health Survey and found that the prevalence of asthma increased with
increasing BMI in women, but not in men. Increasing BMI and
female sex were among the significant predictors of asthma prevalence
in a population-based case-control study with 2788 asthma cases and
39,637 controls (285). The study also found that the risk of having
asthma increased with increasing BMI, with the greatest increase
among individuals with a BMI between 40 and 60 (OR = 2.8; 95% CI,
2.3-3.5), after adjusting for possible confounders including physical
activity. Furthermore, among a few trials, it has been
demonstrated that weight loss can improve lung function in obese
women (286), although the benefit may be limited to patients with
pre-existing asthma. More studies in diverse populations are needed
to confirm that obesity is a significant risk factor for asthma.
3.
Osteoarthritis
Obesity
is a potent risk factor for osteoarthritis, particularly of weight
bearing joints such as the hip and knee (287-290). Although it
is now recognized that the risk factors for the development of
osteoarthritis and the risk factors for the progression of the
disease may not always be the same, obesity may contribute as a risk
factor for both the development and the progression of osteoarthritis
(291). Two possible mechanisms may account for the observed
association between obesity and osteoarthritis: the mechanical
effects on the joint of increased load and/or systemic effects such
as overall bone mineral density or a circulating growth or bone
factor. The suggestion that the association between obesity and
osteoarthritis is a spurious finding due to reverse causation (i.e.
arthritis reduces activity and this in turn results in obesity) is
unlikely. These associations have been seen in prospective
studies (288), in addition to cross-sectional (287, 290)
and case-control studies (292). In
the Framingham Heart Study, initial weight was a strong predictor of
osteoarthritis of the knee, based on X-rays taken at mean age 73 and
after 35 years of follow-up. For men, the relative risk of knee
osteoarthritis was 1.51 (95%CI 1.14, 1.98) in the highest weight
quintile, compared to the lower 3 weight quintile categories.
For women, the relative risks were higher; relative risks of 1.4 (95%
CI 1.1, 1.9) and 2.1 (95% CI 1.7, 2.6) were seen for women in the 4th
and 5th
weight quintiles, respectively (288). A large population-based
case-control study in England (292)
with cases identified prior to surgical
treatment for primary knee osteoarthritis and controls matched
appropriately, reported odds ratios of 2.5 (95% CI 1.8, 3.6) and 6.6
(95% CI 4.4, 10.5) for overweight and obese cases, compared to
respective controls. In this study, a strong monotonically increasing
risk with increasing BMI was observed. The authors emphasize
the public health implications of these strong relative risks in the
face of a common disease; based on their analyses, they estimate that
11% or 24% of cases of knee osteoarthritis would be avoided if
overweight and obese individuals reduced their weight by 2 kg and 5
kg, respectively (292). Accordingly, weight loss has been
recommended as one of the non-pharmacologic standard therapies for
osteoarthritis in overweight patients (American College of
Rheumatology Subcommittee on Osteoarthritis (293). In light of
the recommendation, a recent randomized clinical trial (294)
demonstrated that in older overweight
adults (BMI >28
kg/m2)
with knee osteoarthritis, a combination of modest weight loss and
moderate exercise significantly improved overall physical disability.
Unlike
the strong association demonstrated between obesity and knee
osteoarthritis, the associations between obesity and hip
osteoarthritis have been weaker (295) or
less consistent (296). This difference may reflect
discrepancies in the method for measuring hip osteoarthritis based on
clinical findings (such as hip pain) or radiological description
(297). Preliminary findings of an unpublished prospective study
in Rotterdam (297) have
taken this methodological disagreement into account, suggesting a
strong association (OR = 4.1; 95% CI 2.6, 6.9) between radiological
defined hip osteoarthritis and hip pain for women with BMI >27.4
kg/m2.
Further epidemiological studies are needed to support the link
between obesity and hip osteoarthritis.
4.
Cataract
Age-related
cataract is a major public health problem in the US, affecting
approximately 50% of persons aged 75 years and older (298).
Although the etiology of a cataract is multi-factorial and differs
depending on its location in the lens, obesity is one potential risk
factor that may influence its development. Several
plausible mechanisms exist through which obesity may increase the
risk of cataract. For example, elevated body weight is
associated with increase blood pressure, glucose intolerance and
insulin resistance, three conditions linked with the development of
cataracts.
The
epidemiological evidence linking BMI and cataract has been
inconsistent. Both higher (299-301) and lower BMIs (302, 303)
have been associated with increased risk of certain types of
cataract. Consistent with some reports, Schaumberg and
coworkers (301) observed that BMI was positively associated with risk
of cataract in men. In the same cohort, WHR was also positively
associated with cataract, independent of BMI. Among the
co-morbidities associated with obesity, diabetes has a role as a
biological mechanism linking obesity and cataract, especially with
posterior subcapular (PSC) cataract. Relative to women with
normal fasting glucose concentrations (<7.0 mmol/L), diabetic
women have 31% increased risk of having PSC cataract (OR = 4.1; 95%
CI 1.8, 9.4) (304). In addition, women with BMI >
30 kg/m2
or waist circumference >
89 cm have a higher risk of PSC compare to those with BMI <25
kg/m2
(OR = 2.5; 95% CI 1.2, 5.2) or waist circumference < 80 cm (OR =
2.3; 95% CI 1.0, 5.2). Previous work in the same female cohort
(305) identified that the relative risks of cataract from a 5 kg/m2
increase in BMI were slightly attenuated after adjustment for
diabetes, with female diabetics having 2.88 (95% CI 2.17, 3.81) times
the risk of PSC cataract and males having 2.52 (95% CI 1.52, 4.18)
times the risk compared to non-diabetics. Although it is still
difficult to draw conclusions regarding the role of BMI in cataract
since the etiologies of cataracts differ, existing evidence suggests
that obesity is related to cataract, whether independently or
mediated through other disease pathways.
V
All-cause mortality
In
the context of population-based inquiry, it is difficult to
comprehensively assess the overall effect of obesity on health. One
approach is to examine all-cause mortality. From a methodologic
perspective, this has the advantage of avoiding the issue of
competing risks and misclassification of cause of death. The downside
is that this approach accounts only for the outcome of death, which
represents the most severe form of disease.
Because
of the relative ease of conducting these studies, the early
population-based literature on the health consequences of obesity
contained many articles on the relation of obesity to mortality (31,
248, 306-308). Increasingly, it became obvious that there were
several methodologic flaws that threatened the validity of these
studies. Failure to account for smoking, failure to eliminate the
first several years of follow-up and overcontrol of mediating
variables all tend to attenuate the observed association between
weight status and BMI (309). More recent studies have generally
addressed these pitfalls. In a comprehensive analysis of 5
large prospective studies representing the mortality experience of
almost one million persons, findings were remarkably consistent: the
relative risks become elevated at BMIs between 25 kg/m2
and 29 kg/m2.
At BMI’s in excess of 30 kg/m2
(obesity), a 40 to 60% elevation in risk is observed, and at BMI’s
over 35 kg/m2
(obesity class 2 and 3) the relative risk is approximately 2, or a
doubling of risk (28). Based on 1991 population
characteristics, the authors estimate that in the United States
approximately 300,000 deaths annually are attributable to obesity
(28).
The
role of age in the association of obesity and mortality continues to
be controversial. The debate was sparked when the 1990 USDA Dietary
Guidelines for Americans, which presented separate BMI standards for
adults over and under the age 35, were revised in 1995 to recommend
single guideline that did not vary with age. These guidelines
also recommended that after adult height was reached adults should
not gain more than 10 pounds (310). However, within a ten-year
period, the incidence of major weight gain (5 kg, or 12 pounds) was
3.9% among men and 8.4% among women (311). Evidence was sought
to establish whether the nadir, taken to define optimal weight or
BMI, of the U-shaped weight/mortality curve changed with age.
The debate to resolve became difficult for 2 reasons: 1) the
aforementioned methodologic complexity of the basic relation seemed
to have confused this issue (312) and, 2) there are a limited
number of datasets with adequate data to examine the question. In an
analysis of the mortality experience of approximately 62,000 men and
262,000 women enrolled in the American Cancer Society’s Cancer
Prevention Study I, based on self-reported current height and weight
at baseline, there was no evidence of a shift in the optimal BMI
below age 75. Notable was the observation that with increasing
age the curves became more shallow (313). This flattening of
relative risk occurs because the mortality rate of the entire
population increases markedly with age so that on a “relative
scale” (such as relative risk) the risk due to obesity with
advancing age appears to be reduced. However, as pointed out by
Stevens (312), on an absolute scale (such as risk difference), the
excess number overweight persons continues to increase with age.
Recently, Flegal et al (314) pointed out that the estimates of deaths
attributable to obesity is the US did not necessarily represent the
total US population because of exclusions to control for baseline
health status and the exclusion or under-representation of older
adults. They suggested that a weighted-sum method would provide
more accurate and precise age-specific estimates of mortality risk
for older adults. Hu et al (315) reported concerns that the
arguments by Flegal et al (314) did not take into account chronic,
long-term obesity, as the relative risk calculated from the oldest
age groups would not reflect the true long-term impact of obesity on
mortality.
CONCLUSIONS:
The
health consequences of obesity are substantial, with type 2 diabetes
mellitus, heart disease and gallbladder disease among the more common
obesity-related diseases. The large numbers of children
entering adulthood overweight, together with weight gain in adulthood
portend an enormous burden, in terms of human suffering, lost
productivity, and health care expenditures. The location of fat
is also important and clearly represents a risk factor for
obesity-related disease, independent of overweight; not included in
this review are the considerable psychosocial consequences of
obesity. Given the magnitude of the problem on a population basis,
individual approaches discussed in the remaining chapters will likely
need to be reinforced, supported and extended, by integrated
environmental and policy approaches.
Acknowledgement:
The
authors gratefully acknowledge the assistance of Sarah Phillips,
Marcella Rumawas and Rosaline Bowen. The authors gratefully
acknowledge James B. Meigs, M.D., M.P.H. for his helpful comments.
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