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The Obesity Paradox - and commentary on the Flegal JAMA Study

Abstract

Recently we have been treated yet again to the usual cacophony of poorly informed and misleading headlines, this time based on the systematic review and meta-analysis conducted recently by Katherine Flegal and colleagues at the Centers for Disease Control and Prevention, concerning the "obesity paradox": that overweight and low-grade (grade 1) obesity are not associated with compromised mortality and that being overweight in fact is associated with lower mortality compared to normal weight people. We here critically appraise the evidence base and the study's methodology, to conclude that the balance of critically reviewed and appraised evidence fails to support the contention that overweight is associated with significantly lower all-cause mortality relative to normal weight and that obesity at certain lower levels (grade 1) is not associated with higher mortality, but rather that the cumulative weight of the data to date continue to support the negative impact on health, mortality, and morbidity of being overweight or obese.
Kaniklidis, C. The Obesity Paradox
Copyright © 2013. Constantine Kaniklidis. All rights reserved. 1[publicationpending]
Cancer Research Edge: Critical Commentaries
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The Obesity Paradox
and commentary on the Flegal JAMA Study
Recently we have been treated yet again to the usual cacophony of poorly informed and misleading
headlines, this time concerning the "obesity paradox" - that overweight and low-grade (grade 1)
obesity are not associated with compromised mortality and that being overweight in fact is associated
with lower mortality compared to normal weight people. So from the news media we have, with the
NY Times Health section leading the pack in unsurprisingly hyperbolic fashion: "Study Suggests
Lower Mortality Risk for People Deemed to Be Overweight" (NY Times, 1 Jan 2013), and even more
recklessly from the same source "Our Absurd Fear of Fat" (NY Times, 2 Jan 2013), joining these
others: "Big deal: You can be fat and fit" (CNN, 3 Jan 2013), "Being overweight linked to lower risk
of mortality" (CNN International, 2 Jan 2013), "Few Extra Pounds Won't Kill You—Really" (WSJ, 1
Jan 2013), "Being moderately overweight might not pose health risk" (LA Times, 1 Jan 2013), "Being
overweight may increase odds of living longer" (Fox News, 2 Jan 2013), and from so-called "health" e-
zines we have "Why Do Fat Guys Live Longer?" (Men's Health, 2 Jan 2013), and from even medical
news sources we have "A Few Extra Pounds Linked to a Longer Life" (WebMD, 1 Jan 2013), "A Bit
Of Extra Weight Helps You Live Longer" (Medical News Today, 2 Jan 2013), and with even the
respected NIH's MedlinePlus weighing in with "More evidence for "obesity paradox"" (1 Jan 2013).
Listening to these misinformed voices, we can bemoan the lost art of critical appraisal and the negative
effects of the false assurance these headlines, and the study underlying them, will inevitably have. Let's
critically review the claims and see what's really going on.
Methodological Limitations
The Inadequacy of Body Mass Index (BMI) as a Measure
of Adiposity
There are several significant methodological issues with the
widely cited and - we will show widely misinterpreted -
systematic review and meta-analysis (SR/MA) conducted
recently by Katherine Flegal and colleagues [1] at the Centers
for Disease Control and Prevention on the association between
overweight and obesity, and all-cause mortality using standard
categories of BMI (Body Mass Index). First and foremost is
the choice of BMI as weight metric. In the Iowa Women's Health Study [2], compared to BMI waist
circumference (WC) - a measure of visceral fat which uniquely considers the regional distribution of
adipose tissue on the body - was demonstrated to be superior as a risk indicator for all-cause mortality.
Whereas BMI was associated with mortality in a J-shaped fashion, with mortality rates being elevated
in the leanest as well as in the most obese women, the waist/hip circumference ratio was strongly and
Kaniklidis, C. The Obesity Paradox
Copyright © 2013. Constantine Kaniklidis. All rights reserved. 2[publicationpending]
positively associated with mortality in a strictly dose-response manner. Indeed, clinical guidelines from
the Expert Panel on the Identification, Evaluation, and Treatment of Overweight in Adults [3] have
recommended that when assessing risk of adiposity-related disease, both BMI and waist circumference
should be considered, and the unabated increases in waist circumference (WC) and its the superior
association with obesity are now extensively evidenced (see [14] and references therein).
In this same connection, the Danish Cancer Society (DCS) study from Jane Bigaard and colleagues [4]
found that a 10% larger waist circumference corresponded to a 1.48 times higher mortality over the
entire range of waist circumference, with a dose-response relationship between waist circumference
and mortality for individuals of the same BMI throughout the spectrum (even for those in the normal-
weight range as judged by BMI). Similarly, a meta-analysis [5] of 29 elderly (65 - 74 yrs) cohorts
found that a large WC, defined as 102cm (40.2 inches) in men and 88cm (34.6") in women, was
associated with increased all-cause mortality relative risks for those the overweight and obese BMI
categories compared with the ‘healthy’ weight and a small WC (<94cm (37") in men; <80cm (31.5")
in women) category, showing that in and so in elderly people with an increased WC there were
increased mortality risks - even across BMI categories, and for those who were classified as
‘underweight’ using BMI (see also the REGARDS Study [6]).
These studies collectively contradict the findings of the Flegal SR/MA [1] as to significantly higher
all-cause mortality RR in overweight and obese (grades 2 and 3) BMI categories relative to normal
weight, and further demonstrate the inadequacy of BMI alone as a measure of adiposity.
In addition, in the general population abdominal obesity (waist circumference >88 cm in women and
>102 cm in men) in adults with BMI <35 kg/m2 was associated strongly with multiple cardiovascular
risk factors (CRF), these including hypertension, diabetes, and hyperlipidemia [7, 8], suggesting the
limitation of Flegal study in its restriction solely to all-cause rather than cause-specific mortality. This
is further suggested in the study from Stephen Farrell and colleagues [9] who demonstrated that low
cardiorespiratory risk fitness (CRF) is a stronger predictor than BMI of all-cause mortality in women,
with low CRF in women being an important predictor of all-cause mortality, again suggesting that
BMI as a predictor of all-cause mortality risk in women can be misleading unless CRF is also
evaluated and weighted in.
Kaniklidis, C. The Obesity Paradox
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Confounding
An additional methodological limitation is
failure to control for the aggregate effects
of smoking and reverse causality, that
latter being the state in which diseases lead
to both weight loss and higher mortality.
The Scottish study from Debbie Lawlor
and colleagues [10] that examined the
unbiased association of directly measured
overweight and obesity (based on direct
measurement of weight and height, not
BMI) with all-cause and cause-specific
mortality in two large prospective cohort
studies. With the first 5 years of deaths
removed as control, overweight was associated with an increase in all-cause mortality among never-
smokers (relative risk range = 1.12 to 1.38), while obesity was associated with a doubling of risk in
men in both cohorts and a 60% increase in women. Furthermore, in both never-smokers and current
smokers, being overweight or obese was associated with significant increase in risk of cardiovascular
disease.
These findings demonstrate that with appropriate control for smoking and reverse causality, both
overweight and obesity are associated with important increases in all-cause and cause-specific
mortality, and in particular with cardiovascular disease mortality. What the Scottish study reveals
uniquely is that smoking is in fact itself associated with lower BMI and is moreover strongly
associated with many of the same adverse health outcomes such as diabetes, cardiovascular disease,
and respiratory disease that are likely to show increased incidence in the overweight and obese, and
finally, given the strong association of smoking with reduced BMI, it may be insufficient to wholly
control its effects through the typical simple adjustment for smoking in multivariable models, since for
instance measurement error is effectively inevitable (current smokers may for example identify
themselves as past smokers). In addition, this Scottish study shows that reverse causality - in which
diseases lead to both weight loss and higher mortality - could attenuate the apparent relationship of
obesity to mortality, especially but not exclusively in studies with shorter follow-up periods and/or
inadequate control for critical confounders such as smoking.
The Scottish study [10] therefore demonstrates that reverse causality may induce an appreciable
underestimation of the effect of obesity on all-cause mortality [13], while smoking strongly works to
effectively mask the effects of both overweight and obesity on all-cause and cause-specific mortality,
consequent to both the strong association between smoking and lower BMI, and to the strong effect of
smoking on all-cause, and cause-specific cardiovascular, and cancer mortality, since mortality in those
with lower BMI is increased because of their greater likelihood of being smokers, not because lower
BMI is inconsequential to health. And being either overweight or obese was associated with significant
increases in cardiovascular (particularly from coronary heart disease) and in oncological mortality
among never-smokers, and even in current smokers, being overweight or obese was still associated
with insignificant increase in risk of cardiovascular disease. It is simply that smoking and reverse
causality alone and more powerfully, jointly, mask the true effects of overweight and obesity on all-
cause and cause-specific mortality.
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Limitations of All-Cause Mortality
This also underlines the questionable constraint to all-cause mortality adopted by the Flegal study [1],
rather than assessment of cause-specific mortality from cancer, heart disease or diabetes, given that any
association between weight and mortality for different disease categories may vary with the specific
disease, and moreover may show stronger linkage with weight at lower thresholds of BMI than does
all-cause mortality, not of course neglecting the clear importance of morbidity and disability and
compromised QoL associated with long-term diseases.
Measures of Adiposity
It also neglects to caution the reader that BMI is not itself decisively established as a reliable measure
of unhealthy adiposity (‘fatness’) since it is only metric of height and hence fails to account for other
known disease and mortality factors such as (1) differing fat levels, or (2) differing fat distribution
such as the highly unfavorable "sarcopenic obesity" in which we have elevated fat mass concurrently
with lowered lean / muscle mass), or (3) muscularity, or (4) nutritional balance, among others
(remember highly muscular individual for example can have a high BMI and therefore be categorized
as overweight, while not necessarily carrying significant excess fat). In addition, while BMI reflects
the influence of body height over body weight, it does not reveal body fat percentage (BFP), and it has
been established that body fat percentage (BFP) correlates with risk factors for cardiovascular disease
and metabolic syndrome and hence may be a useful predictor of risk, particularly in metabolically
obese, normal weight individuals [14]. It is clear that focusing of the narrow associative "play"
between BMI and mortality (and more artificially still, only all-cause mortality) is unrepresentative of
real world practice where a wide spectrum of risk factors would assuredly be weighed to assess
mortality (and morbidity) risk, such as hypertension, dyslipidemia, and glucose and insulin dysfunction
among many others, with BMI playing a highly limited role in whole- patient risk evaluations. And it
is now clear that abdominal obesity is more harmful than general obesity: so, for example the risk of
diabetes increases with increases in abdominal fat mass, waist circumference, or waist-to-hip
circumference ratio, and this is in fact independent of BMI value [17. 18], while viscerally deposit fat
as opposed to fat elsewhere in the body is associated with higher risk for hypertension [19], and
abdominal fat mass is a strong risk factor for stroke independent, gain independently of BMI [20].
In addition, Andy Menke and colleagues at Tulane University evaluated the five most common
measures of adiposity - waist circumference (WC), total body fat (TBF), percent body fat (PBF), BMI,
and skinfold thickness - to compare their associations with cardiovascular disease risk factors, finding
that in multivariable adjusted models including waist circumference and BMI as independent variables,
waist circumference was a significantly better predictor of cardiovascular disease risk factors,
including hypertension, diabetes, low HDL-cholesterol, elevated HOMA-IR, and elevated
triglycerides, than other measures of adiposity, among both men and women, findings we note that are
consistent with previous studies that found anthropometric measures that take into account the
distribution of adiposity, specifically abdominal adiposity (as either waist circumference or waist-to-
hip ratio), maintain a stronger association with cardiovascular disease risk factors than BMI [24-30].
Although BMI is widely used as a measure of overweight and obesity, it is known to underestimate the
prevalence of both conditions [24-32], defined as an excess of body fat: thus in the cross-sectional
study conducted by Javier Gómez-Ambrosi and colleagues [31] in Spain, it was found that 29% of
subjects classified as lean and 80% of individuals classified as overweight according to BMI had a
Kaniklidis, C. The Obesity Paradox
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body fat percentage within the obesity range, yielding elevated concentrations of cardiometabolic risk
factors in non-obese individuals when classified by BMI but obese based on body fat measurement.
Again the same team [33] confirmed in another study that there is a high degree of misclassification in
the diagnosis of obesity using BMI in clinical practice, resulting in the underdiagnosis of obese
patients at risk and hence yielding missed opportunities to treat this life-threatening condition (32% of
lean and 82% of overweight subjects as classified by BMI were in fact obese according to body fat
percentage), and for prediabetes and type 2 diabetes development, especially in lean subjects classified
by BMI and in males in particular, body fat percentage appears to be more determinant than BMI and
even than waist circumference. And the Canadian study from Jennifer Shea and colleagues [35] also
confirmed that those with elevated body fat percentage are at increased risk of developing
cardiometabolic disease despite having a normal BMI. This was further put to the test, reconfirming
our own review's conclusion that BMI is an imprecise and significantly inadequate adiposity metric, by
Dale Okorodudu and colleagues [34] in a systematic review and meta-analysis of 25 studies that met
the predefined inclusion criteria, spanning 32 different samples totaling 31,968 patients, who
demonstrated that the commonly used BMI cutoff values to diagnose obesity had high specificity but
low sensitivity for identifying adiposity, given that they fail to identify half of the people with excess
body fat percentage.
But still further and critical erosion of the Flegel study's conclusions come from the recent NCI
prospective cohort study from Yikyung Park and NCI co-researchers [11] who performed a
prospective analysis using data from 183,211 adults aged 45–75 who enrolled in the population-based
Multiethnic Cohort Study. This NCI review exercised uncommonly effective control for confounding
from conditions that lead to weight loss and mortality by excluding participants (1) with a history of
cancer or heart disease, (2) who ever smoked, and (3) who died within the first 3 years of follow-up.
Under those controls, an increased risk of mortality was observed in participants with a BMI 27.5 in
both men and women compared with the reference category of BMI 23.0–24.9 (with a BMI 35.0
carrying a greater risk of mortality in men than in women), so that among healthy never smokers, adult
overweight and obesity were both associated with increased risk of mortality in both genders,
confirming the findings of the other tightly controlled study just discussed, the Scottish study.
Kaniklidis, C. The Obesity Paradox
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Clinical Lessons
Therefore, the balance of critically reviewed and appraised evidence fails to support the contention of
the Flegal study that overweight is associated with significantly lower all-cause mortality relative to
normal weight and that obesity at certain lower levels (grade 1) is not associated with higher mortality,
but rather the cumulative weight of the data to date continue to support the negative impact on
health, mortality, and morbidity of being overweight or obese. And in this connection, it must be also
remembered that intentional weight loss does in fact result in a decreased incidence of cancer,
particularly female obesity-related cancers [12] and so the seductive but misleading findings of the
Flegal study should not lull us into a false security and diminish the very real motivations for
maintenance of health-favorable weight along with other dietary and lifestyle interventions.
With the prevalence of obesity being greater than 20% in many developed countries and increasing in
developing countries, and with obesity being unambiguously associated with metabolic disorders,
especially diabetes, cardiovascular diseases, pulmonary diseases, digestive diseases, and cancers, it is
clear that weight loss must remain the central defense against the pandemic, associated with an
increased risk of death, morbidity, and accelerated aging [23], of obesity [15], “diabesity” (the
designation for the continuum of abnormal metabolic biologies from mild insulin resistance to
established diabetes that includes any insulin dysfunctions secondary to obesity), and metabolic
syndrome, and no one should, through the compromised methodologies and against-the-weight-of-the-
evidence conclusions we have demonstrated within the Flegal study, sustain the illusion that
overweight or obesity is other than detrimental and contributory to morbidity and mortality, both all-
cause and cause-specific, within the context of these rising and unabated pandemics. We need such
clear recognition to help avoid or mitigate what is expected to be the future obesity for adults in the
United States, namely that by 2030 (as projected from the National Health and Nutrition Examination
Study (NHANES)), 86.3% American adults will be overweight or obese, and 51.1% of them will be
obese, with total health-care costs attributable to obesity/overweight doubling each decade to 2030 and
accounting for 16–18% of total US health-care costs [16]. And overweight and obesity could account
for 14% of all deaths from cancer in men and 20% of deaths in women as shown a prospective study of
900,000 US adults [21]. Therefore, as these considerations show, both overweight and obesity cause
huge burdens for patients, family, and for society, locally and globally and cannot legitimately be
perceived as in any way healthful. It will take a wide spectrum of coordinated health professionals,
public education, sophisticated research into diagnostic and therapeutic tools and interventions, and
proactive national policies to launch integrative and targeted initiatives to materially influence and
slow these pandemics in obesity, diabesity and metabolic syndrome.
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Anthropometric measures such as the body mass index (BMI) and waist circumference are widely used as convenient indices of adiposity, yet there are limitations in their estimates of body fat. We aimed to determine the prevalence of obesity using criteria based on the BMI and waist circumference, and to examine the relationship between the BMI and body fat. This population-based, cross-sectional study was conducted as part of the Geelong Osteoporosis Study. A random sample of 1,467 men and 1,076 women aged 20-96 years was assessed 2001-2008. Overweight and obesity were identified according to BMI (overweight 25.0-29.9 kg/m²; obesity ≥30.0 kg/m²) and waist circumference (overweight men 94.0-101.9 cm; women 80.0-87.9 cm; obesity men ≥102.0 cm, women ≥88.0 cm); body fat mass was assessed using dual energy X-ray absorptiometry; height and weight were measured and lifestyle factors documented by self-report. According to the BMI, 45.1% (95%CI 42.4-47.9) of men and 30.2% (95%CI 27.4-33.0) of women were overweight and a further 20.2% (95%CI 18.0-22.4) of men and 28.6% (95%CI 25.8-31.3) of women were obese. Using waist circumference, 27.5% (95%CI 25.1-30.0) of men and 23.3% (95%CI 20.8-25.9) of women were overweight, and 29.3% (95%CI 26.9-31.7) of men and 44.1% (95%CI 41.2-47.1) of women, obese. Both criteria indicate that approximately 60% of the population exceeded recommended thresholds for healthy body habitus. There was no consistent pattern apparent between BMI and energy intake. Compared with women, BMI overestimated adiposity in men, whose excess weight was largely attributable to muscular body builds and greater bone mass. BMI also underestimated adiposity in the elderly. Regression models including gender, age and BMI explained 0.825 of the variance in percent body fat. As the BMI does not account for differences in body composition, we suggest that gender- and age-specific thresholds should be considered when the BMI is used to indicate adiposity.
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