Health Benefits of Long-Term Weight-Loss Maintenance

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ANNUAL
REVIEWS Further Health Benefits of Long-Term
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• Our comprehensive search and Arya M. Sharma∗
Annu. Rev. Nutr. 2015.35:475-516. Downloaded from www.annualreviews.org
Access provided by 115.132.168.111 on 05/01/20. For personal use only.
Obesity Research & Management, Clinical Research Unit, Department of Medicine, Faculty of
Medicine and Dentistry, University of Alberta, Edmonton, Alberta, T6G 2E1 Canada;
email: ruedacla@ualberta.ca, aogunley@ualberta.ca, amsharm@ualberta.ca
Annu. Rev. Nutr. 2015. 35:475–516 Keywords

First published online as a Review in Advance on bariatric, obesity, bypass, diet, outcomes
May 13, 2015
The Annual Review of Nutrition is online at Abstract

nutr.annualreviews.org
Obesity is a chronic and complex medical condition associated with a large
This article’s doi: number of complications affecting most organs and systems through multiple
10.1146/annurev-nutr-071714-034434
pathways. Strategies for weight management include behavioral, pharmaco-
Copyright c 2015 by Annual Reviews. logical, and surgical interventions, all of which can result in a reduction in
All rights reserved
obesity-related comorbidities and improvements in quality of life. However,
∗
Corresponding author subsequent weight regain often reduces the durability of these improve-
ments. The objective of this article is to review evidence supporting the
long-term effects of intentional weight loss on morbidity, mortality, quality
of life, and health-care cost. Overall, considerable evidence suggests that
intentional weight loss is associated with clinically relevant benefits for the
majority of obesity-related comorbidities. However, the degree of weight
loss that must be achieved and sustained to reap these benefits varies widely
between comorbidities.
475
Contents
1. INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 476
1.1. Assessing Patients with Obesity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 477
1.2. Successful and Sustained Weight Loss Definition and Limitations . . . . . . . . . . . . 481
1.3. The Therapeutic Framework for Weight Loss . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 482
1.4. Weight Management Beyond Weight Loss . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 484
2. EFFECT OF SUSTAINED WEIGHT LOSS ON MAJOR
CARDIOVASCULAR DISEASES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 485
2.1. Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 485
2.2. Coronary Artery Disease, Acute Coronary Syndromes,
and Stroke/Transient Ischemic Attack . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 487
3. EFFECT OF SUSTAINED WEIGHT LOSS ON DIABETES
AND GLUCOSE METABOLISM . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 488

3.1. Weight Change and Risk of Developing Diabetes

in Individuals with Prediabetes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 488
3.2. Effect of Sustained Weight Change in Individuals with Type 2
Diabetes Mellitus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 490
4. EFFECT OF SUSTAINED WEIGHT LOSS ON LIPID HOMEOSTASIS . . . . . 491
5. EFFECT OF SUSTAINED WEIGHT LOSS ON
GASTROINTESTINAL OUTCOMES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 492
5.1. Nonalcoholic Fatty Liver Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 493
5.2. Hepatobiliary Disease/Gallstones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 494
6. EFFECT OF SUSTAINED WEIGHT LOSS ON OSTEOARTHRITIS
AND CHRONIC PAIN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 494
7. EFFECT OF SUSTAINED WEIGHT LOSS ON RESPIRATORY HEALTH . . 495
7.1. Obstructive Sleep Apnea . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 495
7.2. Obesity Hypoventilation Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 496
7.3. Chronic Obstructive Pulmonary Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 497
7.4. Asthma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 497
FERTILITY/PREGNANCY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 498
9. EFFECT OF SUSTAINED WEIGHT LOSS ON URINARY
AND FECAL INCONTINENCE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 499
10. EFFECT OF SUSTAINED WEIGHT LOSS ON CANCER PREVALENCE
AND MORTALITY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 499
11. EFFECT OF SUSTAINED WEIGHT LOSS ON MENTAL HEALTH . . . . . . . 501
ALL-CAUSE MORTALITY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 502
13. EFFECT OF SUSTAINED WEIGHT LOSS ON QUALITY OF LIFE . . . . . . . . 503
14. CONCLUSIONS AND OUTLOOK . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 504
1. INTRODUCTION
Obesity is estimated to affect over 700 million people worldwide (165). Obesity holds a close second
place among the main causes of preventable death (following tobacco use), with US health-care
expenses estimated to be over $147 billion in 2009 (60). Recent epidemiological data suggest that
476 Rueda-Clausen · Ogunleye · Sharma

the rapid increase in the prevalence of obesity observed during the 1980s and 1990s has slowed
down or even plateaued in some developed countries over the last decade (58, 149). However, a
different analysis of this data shows that the prevalence of more severe cases of obesity continues to
BMI: body mass index
rise rapidly in most countries (61). Thus, clinical encounters with individuals presenting with severe
[body mass index (BMI) >40 kg/m2 ], super (BMI >50 kg/m2 ), super-super (BMI >60 kg/m2 ), and
super-super-super (BMI >70 kg/m2 ) obesity pose an increasing challenge to health-care systems.
Over the past few decades, cross-sectional and cohort studies have increased our understanding
of weight-loss interventions and their impact on health. The aim of this review is to summarize and
discuss the effects of long-term weight loss on health and disease and to consider some fundamental
questions, including the setting of weight-loss targets, the risks and benefits of sustaining long-
term weight loss, and the issue of realistic expectations in a weight management program.
1.1. Assessing Patients with Obesity

Despite the rather succinct definition of obesity as a medical condition in which excess body fat
has accumulated to the extent that it may have an adverse effect on health (84), the screening,
assessment, and diagnosis of individuals with obesity can be a very complex process involving
a wide range of interconnected factors including societal, psychological, and biological drivers
of weight gain; weight history; impact of excess weight on mental, mechanical, metabolic, and
monetary health; as well as quality of life of individuals living with obesity (186). In addition,
consideration must be given to rare syndromal forms of obesity and obesogenic medications as
well as the variable anatomical and morphological features of body fat.
Historically, a multitude of anthropometric parameters have been proposed to define and
measure obesity. A list of the most commonly used parameters is presented in Table 1 (73, 92,
217). Nevertheless, the heterogeneous nature of fat distribution and its variable impact on health
continue to challenge the validity and relevance of these anthropometric parameters, especially
when applied to individual patients in clinical practice. More recent technological developments
include dual X-ray absorptiometry, air displacement densitometry, bioelectrical impedance, ul-
trasonography, body water estimates, magnetic resonance imaging/spectroscopy, and computed
tomography, all of which provide more precise methods for measurement of body fat content and
distribution (217). However, these methods have yet to find their way into clinical practice. More
recently, ectopic fat contained within nonadipose tissues or organs (e.g., liver, skeletal muscle)
has emerged as a possible surrogate measure of fat deposition with particular relevance for the
metabolic complications of obesity (217). Overall, the exact clinical definition and characterization
of obesity continue to evolve and take into account the distribution and function of adipose tissue
as well as its impact on health and well-being.
Currently, body weight, BMI, and the rather unfortunate term “excess body weight” (102)
continue to be the most commonly used parameters to screen, assess, and manage obesity. The
downside of these measurements is that they perform poorly when compared to other anthro-
pometric or more direct methods to measure body fat content and/or body fat distribution (67).
Moreover, changes in anthropometric parameters correlate rather poorly with changes in certain
major health outcomes [such as cardiovascular morbidity, mortality (171), and quality of life (154)].
It is also important to note that lower cutoffs for BMI have been proposed for South Asian and
East Asian populations, which appear to be at far greater risk of developing obesity-related health
problems than other ethnic groups at a given BMI (228).
The recognition that in a given individual, there is often little relationship between the magni-
tude of obesity (as assessed by anthropometric measures) and the impact of body fat on measures
of health or functioning has prompted the development of clinical staging tools to better assess
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Table 1 Parameters frequently used for the assessment of obesity

ARI
Parameter Measurement/estimation Obesity cutoff Advantage Limitations
478
Body weight First time in the morning, empty bladder, >90th percentile for sex, age, race Inexpensive, portable, Does not discriminate body
light clothing (kg) reproducible composition or fat
distribution
6 June 2015
Weight-to- = W (kg)/H (m) N/A Inexpensive, portable, Minimal validation

height ratio reproducible
Rueda-Clausen
(W/H)
·
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Quetelet index = W (kg)/H (m)2 Overweight >25 kg/m2 Widely used; height corrected Does not discriminate body
[body mass Obesity class 1 >30 kg/m2 composition or fat
Ogunleye
index (BMI)] (>25 kg/m2 for Japanese people) distribution
·
(163) (57), class 2 >35 kg/m2 , class 3 Originally aimed for
>40 kg/m2 , class 4 (super obese) epidemiological studies and
Sharma
>50 kg/m2 , class 5 (super-super population surveys but not
obese) >60 kg/m2 , class 6 (super- for assessment of obesity
super-super obese) >70 kg/m2
Khosla-Lowe = W (kg)/H (m)3 >65 Highly correlated with BMI N/A
index and total body fat
Benn index = W(kg) / H(m)p N/A Highly correlated with BMI N/A
Exponent p is a population-specific and total body fat
variable
Four- Fat mass = 2.513 × BV − 0.739 × >25% men N/A Complex, expensive
compartment TBW + 0.947 × TBBM − 1.79 × BW >35% women
body BV, body volume as measured by
composition hydrodensitometry; TB, total body
model water as measured by hydrometry;
TBBM, total body bone mineral mass as
measured by DEXA
Excess body Amount of weight that is in excess of the Obese class 1 >20% of IBW N/A N/A
weight ideal body weight (IBW), which derived Obese class 2 >100% of IBW
(EBW)% from the 1983 Metropolitan Insurance Super obese >250% of IBW
height and weight tables (132) or weight
above BMI of 25 kg/m2 .
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Anthropometric Men: >25% men Very sensitive to changes in Low sensitivity to weight
s t)−(0.082×W ))
estimation of = 100×(−98.42+(4.15×W
W >35% women waist change
ARI
percent body Women:

s t)−(0.082×W ))
fat = 100×(−76.76+(4.15×W
W
Waist Standing, abdomen exposed, place a Race specific Good predictor of Limited reproducibility
circumference measuring tape placed parallel to the Male from 85 to 102 cm intra-abdominal fat content
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floor at the level of the anterior superior Female from 80 to 90 cm

iliac crest; measure at the end of normal
expiration
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Waist circumference
Waist to hip Hip circumference
>1 in men and >0.85 in women Good predictor of Limited reproducibility
ratio intra-abdominal fat content
and cardiovascular risk
W s t(c m)
Waist-to- H (c m) × 100 >50% More adequate for nonobese Low reproducibility
stature ratio and people with very low fat
(WSR)% content, such as
bodybuilders (148, 178)
Body adiposity (BAI = ((hip circumference)/ >25% male Close correlation with body Requires adequate hip
index (BAI) ((height)1.5) − 18)) >39% female fat content circumference measurement
(13)
Skinfold Variety of models and equations N/A Inexpensive, noninvasive Timely; large variability;
thickness requires highly trained
personnel for measurement;
unreliable in severely obese
people
Bioelectric Estimate based on body total resistance to >25% men Fast, easy, reproducible Not accurate in severe
impedance small voltage current (typically 800 μA, >35% women obesity; fluctuates based on
50 kHz) hydration status
Underwater Assuming that fat is less dense than lean >25% men Very accurate Expensive; time consuming;
weighing tissue, it estimates based on body weight >35% women complicated; patient has to
(densitometry) changes after immersion in water be under water
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Cannot discriminate fat
location; affected by residual
479
lung volume estimations
(Continued )
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ARI
480
6 June 2015
Table 1 (Continued )
Parameter Measurement/estimation Obesity cutoff Advantage Limitations
Rueda-Clausen
·
Air- Estimate based on air displacement using >25% men Accurate, no immersion Expensive; requires special
13:11
displacement the same principle as densitometry >35% women required equipment

plethysmogra- Cannot discriminate fat
Ogunleye
phy location
·
Isotope dilution Radioactive isotopes distribute freely >25% men Relatively inexpensive; safe in Cannot discriminate fat
method through body compartments and dilute >35% women pregnancy and childhood location
Sharma
(hydrometry) proportionally to the amount of total
body water. Estimation of body fat is
based on the assumption that the
proportion of water to lean tissue is
relatively stable (0.73)
Dual-energy Using dual low-energy X-ray penetration, >25% men Safe in childhood; not safe in Cannot discriminate fat
X-ray it estimates body lean tissue, fat, and >35% women pregnancy; highly location
absorptiometry bone density in different regions (arms, reproducible
legs, and trunk)
Computerized Using high-resolution images and >25% men CT and MRI are the most Expensive; in the case of CT,
tomography dedicated software for data extraction, it >35% women accurate methods for implies radiation; most
(CT) and estimates the volume of fat tissue and assessing body composition equipment cannot
magnetic even intraorgan or intercellular fat accommodate very obese
resonance content subjects
imaging (MRI)
obesity in individuals. These systems include the King’s Criteria, which defines the severity of
obesity based on how it affects a list of factors and organ systems (2), and the Edmonton Obesity
Staging System, which classifies individuals on a five-point ordinal scale based on the presence
and severity of mental, medical, and functional complications of excess weight (154). The latter
system, which proves a better predictor of mortality than BMI, waist circumference, or metabolic
syndrome (154), has now been included in practice recommendations by the American Society
of Bariatric Physicians (114) and the Canadian Obesity Network (118). A similar approach that
stages obesity on the presence of additional risk factors and complications has been proposed in a
treatment algorithm by the American Association of Clinical Endocrinologists (68).
Despite their obvious limitations, anthropometric-based definitions of obesity continue to be
widely used in epidemiological and clinical studies, with little consideration given to the rather
complex and heterogeneous etiology of this condition or to the highly variable clinical phenotype,
which can range from metabolically healthy obese individuals (21) to individuals with a wide range
of coexistent mental and physical comorbidities and/or functional limitations.
In light of this rather unsatisfactory definition of obesity, it is important to note that for the
purposes of this review we use the most common definition of obesity based on BMI (>30 kg/m2 ).
Where possible, we have given additional consideration to findings in individuals with more
extreme obesity (such as in individuals undergoing bariatric surgery).
1.2. Successful and Sustained Weight Loss Definition and Limitations

The precise definition of success in terms of weight loss remains controversial. Similarly unclear
are the length of follow-up and the range of weight fluctuation that is acceptable as a sustained
effect. In the face of this diagnostic dilemma, Wing & Hill (238) previously proposed an arbitrary
definition for successful weight loss as a function of intentionality, magnitude (weight loss greater
than 10% of the initial body weight), and temporal sustainability (greater than 12 months). The
10% cutoff point used by these authors was justified by early observational studies showing that
such a magnitude of weight loss was associated with a significant decrease in the prevalence of car-
diometabolic risk factors. Despite being poorly supported by clinical evidence, these cutoff points
have been extensively adopted in clinical and experimental protocols over the past few decades
(142, 225). Alternative cutoff points (3%, 5%, or 20% weight loss) and different anthropometric
criteria (such as excess body weight, total body fat content, or intra-abdominal adiposity) have also
been suggested by numerous authors, but appropriate studies comparing the different definitions
are still lacking.
The National Weight Control Registry is an initiative aimed at identifying the common de-
nominators of successful weight losers (arbitrarily defined as intentional weight loss >30 pounds
for a period of >12 months). The vast majority of individuals in the National Weight Control
Registry manage to sustain a weight loss greater than 10% of their maximum weight, which is as-
sociated with a significant improvement in several relevant health outcomes over extended periods
of time (208). However, they also report eating severely restricted diets (less than 1,500 kcal/day),
vigorous daily exercise regimens (approximately 400 kcal/day), and rather drastic changes to their
overall lifestyles, including in their social and personal interactions (22). It is therefore unclear
whether findings from this registry can be extrapolated to a more general population with obesity
or to which extent any reported health outcomes are attributable to weight loss rather than to
other changes in lifestyle or psychosocial context.
From a therapeutic perspective, the efficacy benchmarks proposed by the US Food and
Drug Administration (FDA)—in its guidelines for the development of products for weight
management—state that a product for weight management is effective if (a) after one year of

use it causes an additional 5% initial body weight loss compared to placebo or (b) the proportion
of subjects achieving more than 5% of initial body weight loss is greater than 35% and approxi-
mately twice as high in the group receiving the experimental medication in comparison to those
in the control group receiving placebo. However, the FDA also states that the effects of novel in-
terventions in obesity-related comorbidities should be factored in the assessment of effectiveness
(45).
Despite the absence of consensus, any intentional reduction in body weight or adiposity (or
even a reduction in further potential weight gain) in patients with obesity seems to be associated
with a proportional and direct health benefit. Specific cutoff points defining a clinically meaning-
ful weight/adiposity change, however, may vary depending on the outcome of interest and the
characteristics of the patients.
Adding further complexity to the definition of successful weight loss, the timing and significance
of weight trajectories are rarely described or discussed in the literature. The dogmatic assumption
that longer periods of sustained weight loss are more likely to have a beneficial effect on health
outcomes has never been challenged. Experimental models have shown that rodents experiencing
pronounced and rapid fluctuations in weight can exhibit worse phenotypes (e.g., increases in
blood pressure or blood glucose levels) than those with a sustained progressive weight gain (11,
51). However, human data on the impact of weight cycling from intervention trials are sparse.
Nevertheless, some findings in humans suggest that even short-term weight loss may result in
longer-term benefits through a so-called legacy effect or metabolic memory effect (34).
1.3. The Therapeutic Framework for Weight Loss

Current interventions for weight management can be grouped in three major categories: behav-
ioral, pharmacological, and surgical. Each has advantages and limitations (3, 46).
Behavioral (or lifestyle) interventions including diet and exercise are very effective in achieving
weight loss in the short term (as much as 15% to 25% of initial body weight within three to
six months) (211). However, in most cases the benefits of these behavioral approaches are not
sustainable in the long term (65). On average, subjects undergoing behavioral interventions re-
gain close to 30% of their initial weight loss in the first 12 months after discontinuation of the
intervention (65). Overall, large trials in which intensive lifestyle interventions were implemented
(often at experienced academic centers) resulted in 4% to 5% weight loss during the first year,
with maintenance of approximately 2% weight loss after two years (65). More recently, the Dia-
betes Support and Education Intervention and its Action for Health in Diabetes (Look AHEAD)
trial (236), which followed 5,145 subjects with type 2 diabetes over ten years to assess the effect of
intensive diet and exercise intervention (compared to standard care) to reduce weight and improve
cardiovascular morbidity and mortality, showed that intensive behavioral interventions can lead to
a sustained intentional weight loss (4.7% ± 0.2% versus 2.1 ± 0.2% of initial weight, respectively
p < 0.001) and an increased likelihood of achieving a sustainable weight loss ≥10% of initial body
weight (26.9% versus 17.2%, respectively, p < 0.001) for a prolonged period of time (up to eight
years) (124).
Despite their modest effect on long-term weight loss, lifestyle modifications that include im-
proving eating behaviors and increasing physical activity constitute a cornerstone for integral and
sustainable weight management (113). This is mainly because of other weight-independent bene-
fits on health and the synergistic effect of lifestyle modifications on pharmacological and surgical
interventions for weight management (225).
More sophisticated behavioral interventions such as cognitive behavioral therapy have also
proven to be effective in the short-term management of obesity, particularly in cases in which

Lifestyle and
0 pharmacologic
–5
Relative change
–10
–20
–40
Lifestyle Surgery
0 2 4 6 8 10 20 30 40
Sustained weight loss (kg)

Systolic BP (mmHg) Fasting glucose (% change)

Diastolic BP (mmHg) Total cholesterol (% change)
Breast CA (relative risk reduction) Triglycerides (% change)
T2DM (incidence per 100 person/years)
80 Lifestyle and
pharmacologic
60
Relative change
40
20
0
Lifestyle Surgery
0 2 4 6 8 10 20 30 40
Sustained weight loss (kg)
Absolute change in proportion of subjects at A1c target (%)

Dyslipidemia remission rates (%)
NAFLD relative prevalence reduction (%)
Figure 1
Summary of the most significant health effects of sustained weight reduction. Abbreviations: A1c,
hemoglobin A1c; BP, blood pressure; CA, cancer; NAFLD, nonalcoholic fatty liver disease; T2DM, type 2
diabetes mellitus.
eating disorders (binge eating, night eating, emotional eating, etc.) are major drivers of weight
gain (232). The long-term effectiveness of these interventions in terms of weight loss, however, is
only marginally better than that of diet and exercise alone (212).
One step further along the invasiveness/effectiveness scale (Figure 1) lies a growing arsenal of
pharmacological options (123). These include the traditional medications phentermine and orlistat

and a new group of oral medications that includes lorcaserin, phentermine-topiramate extended
release (PhenTop-ER), naltrexone sustained release-bupropion sustained release (NaltBup-SR),
and an injectable glucagon-like peptide-1 analogue (liraglutide) that was recently approved by the
SG: sleeve
gastrectomy FDA for obesity management (8). In combination with behavioral interventions, these pharma-
cologic agents result in an additional weight loss ranging between 2% and 10% of initial body
RYBG: Roux-en-Y
gastric bypass weight (for reviews, see 176, 222).
The third and most invasive category of weight management interventions includes a range of
surgical procedures that are often referred to as bariatric or weight-loss surgery (163). The tech-
nical details of these procedures are in constant evolution but have traditionally been described
as either restrictive [including laparoscopic adjustable gastric banding (LAGB), vertical banded
gastroplasty, and laparoscopic sleeve gastrectomy (SG)] or malabsorptive [such as roux-en-Y gas-
tric bypass (RYGB), and biliopancreatic diversion]. The detailed mechanisms that promote and
sustain weight loss after bariatric surgery remain a matter of ongoing research (202).
Nevertheless, with significant advances and experience in minimally invasive surgery, all of
these procedures are now considered safe (estimated 30-day postoperative mortality between 80
and 220 per 100,000 procedures) (33) and effective in producing a significant and sustainable
weight loss (approximately 15–30% body weight loss after 10 years) (196) accompanied by often
substantial improvements in health outcomes such as diabetes, cardiovascular events, and quality
of life (162). The growing evidence on the long-term benefits of bariatric surgery has led to a
proliferation of bariatric surgical programs and bariatric surgical procedures around the world.
According to one report, bariatric surgery recently became the most common elective abdominal
surgery performed in United States (201). Nevertheless, given the limitations of both cost and
the surgical capacity in most health systems, bariatric surgery can accommodate only a minute
fraction of eligible patients (153).
Together with patients’ expectations, motivations, and past experiences, other major factors
to be considered by providers involved in bariatric care include the benefits as well as potential
adverse effects of weight-loss interventions on obesity-related comorbidities and other relevant
health outcomes. The benefits and potential adverse effects associated with different weight-loss
interventions are an area of active research due to the ongoing influx of new pharmacological
and surgical techniques, increasing experience of medical and surgical teams, and changes in the
availability of these treatments within health systems (12).
1.4. Weight Management Beyond Weight Loss

Several factors make it difficult to determine the independent effect of weight loss on health
outcomes. Weight-loss interventions are generally accompanied by profound changes in diet
and/or physical activity, both of which may have complex independent effects on health outcomes.
Thus, it is virtually impossible to determine whether improvements in health associated with
weight loss are attributable to a reduction in body fat or simply the metabolic consequences of
negative energy balance and/or changes in diet and physical activity. In addition, comparable
changes in body weight, or even body fat content, can have very different effects on insulin
sensitivity depending on the intervention used to produce weight change (regular exercise versus
low-fat diet versus liposuction). This may explain why significant improvements in health outcomes
can often be seen with minimal weight loss (as little as 3–5%) and the overall correlation between
the degree of weight loss and the improvements in health outcomes seen in many studies is rather
poor (171, 197).
The complex interaction between obesity and other cardiovascular risk factors constitutes a
limiting factor for the accurate estimation of the independent effect attributable to weight loss

alone; therefore, most approximations to this question have been made under the likely equivocal
assumption that, gram by gram, changes in body weight (or any other anthropometric parameter)
lead to a predictable change in the amount, distribution, and function of adipose tissue.
Unintentional weight loss in some subjects (e.g., due to smoking or a comorbid condition)
potentially adds a further level of complexity to this particular question and may contribute to
noise in most epidemiological and nonexperimental (nonrandomized) studies. This may well be
the explanation for the so-called obesity paradox, where excess weight has been associated with
improved survival in individuals with other chronic diseases (e.g., heart failure, end-stage renal
failure, chronic obstructive lung disease).
2. EFFECT OF SUSTAINED WEIGHT LOSS ON MAJOR

CARDIOVASCULAR DISEASES
Several pathophysiological mechanisms have been implicated in the interaction between obe-
sity and cardiovascular disease. Overall, these mechanisms can be grouped as hemodynamic or
metabolic.
The hemodynamic mechanisms associated with weight gain include an increase in circulating
volume and increase in cardiac output often followed by an increase in peripheral vascular resis-
tance. The persistence and chronicity of these hemodynamic changes trigger a number of cardiac
remodeling responses that lead to hypertrophic and/or dilated cardiomyopathy (101), depending
on whether the predominant offender is increasing peripheral resistance or volume overload, re-
spectively. The resulting induction of myocardial remodeling can cause myocardial fibrosis and
subsequent diastolic dysfunction (due to increased ventricular stiffness) as well as structural changes
in the electrical conductance fibers, all of which contribute to a higher risk of developing cardiac
arrhythmias (131).
The metabolic mechanisms associated with weight gain include insulin resistance often accom-
panied by hyperinsulinemia, impaired glucose tolerance, and eventually type 2 diabetes as well as
atherogenic dyslipoproteinemias, fatty liver disease, prolonged QT interval (89), myocardial fatty
infiltration with impaired myocardial energetic efficiency (147), and increased thrombogenesis
(169). In addition, obesity-related hypoventilation syndromes (e.g., chronic hypercapnia and ob-
structive sleep apnea) have been associated with increased cardiovascular morbidity and mortality
(150).
A large number of observational studies suggest that the prevalence of cardiovascular disease
and the incidence of acute atherothrombotic events can be reduced through long-term intentional
weight loss (172, 173, 179, 180, 198, 224). However, many questions about the amount and
duration of weight loss required to produce a significant effect on cardiovascular outcomes, as well
as the impact of different strategies to achieve and sustain weight loss, remain unresolved.
2.1. Hypertension
The association between obesity and the risk of developing hypertension (234) as well as the blood
pressure–lowering effect of weight-loss interventions (82) are well documented. A meta-analysis
by Staessen and collaborators (199) that included 12 studies (mostly nonrandomized) estimated
that among hypertensive and obese subjects, each kilogram of intentional and sustained weight loss
is associated with a 1.2 mm Hg and 1.0 mm Hg reduction in systolic and diastolic blood pressure,
respectively. Similar findings were replicated by Neter et al. (140) in a meta-analysis of 25 trials of
nonpharmacologic weight-loss interventions (4,874 subjects, average follow-up 66.6 weeks; only
two studies overlapped with the Staessen et al. analyses) resulting in an estimated 1.05 systolic and

0.92 mm Hg diastolic blood pressure reduction per kg of weight loss. However, in a systematic
review that included seven weight-loss trials (with observation periods greater than two years),
Aucott et al. (9) reported that the attributable antihypertensive effect of weight loss (via nonsurgical
RCT: randomized
controlled trial means) is only approximately half as large as previously described in short-term studies (−6.0 mm
Hg in systolic and −4.6 mm Hg in diastolic blood pressure for 10 kg of weight loss). The same
authors also reported eight studies exploring the same question among people with less severe
obesity (BMI <35 at baseline) and observed that a 5 kg weight loss in this population may have a
reduction effect on systolic blood pressure of approximately 5.6 mm Hg (10). Common limitations
recognized by all the abovementioned authors includes the extensive heterogeneity in study design,
interventions, and outcomes; the potential confounding effect of changes in sodium intake and
physical activity; and the often short observational periods of these studies. The latter is important,
as there are data to suggest that the state of negative energy balance during weight loss may have
a more profound effect on blood pressure than the state of neutral energy balance that is achieved
when participants attain a new, albeit lower, stable weight as a result of the intervention (82).
More recently, the Look AHEAD study (124), in which the mean maximal weight loss in
the intervention group was 8.6% for the first year and 4.7% at four years (compared to 1.1%
in the control group) (236), reported an extra reduction of 2.4 mm Hg systolic and 0.4 mm Hg
diastolic blood pressure at four years. However, the proportion of subjects achieving target blood
pressures after four years was comparable between groups (61% versus 63%) (236). These finding
are difficult to interpret given that there were substantial differences between experimental groups
in the proportion of subjects receiving blood pressure medications and the amount of medications
required for blood pressure control at the end of the study (99).
Although greater weight loss can be achieved by adding pharmacological therapy to behavioral
interventions, the blood pressure effect of these medications can vary depending on their mode of
action. A meta-analysis that included 16 randomized controlled trials (RCTs) for orlistat versus
placebo (10,631 patients) showed an additional weight-loss effect of 2.9 kg and additional systolic
blood pressure reduction of 1.5 mm Hg after one year (174). Three small RCTs that followed
patients on orlistat or placebo for two years showed similar results (9). Participants on lorcaserin,
in three clinical trials (approximately 2,000 subjects followed for at least one year), showed an
additional 3 kg weight loss compared to a lifestyle-alone intervention and a modest systolic blood
pressure reduction effect of 0.6 mm Hg (176). Patients on PhenTop-ER, in two large RCTs
(approximately 3,000 patients followed for one year), showed an additional 8.8 to 10.8 kg weight
loss compared to intervention with placebo plus lifestyle recommendations and an additional
reduction in systolic blood pressure of 3.8 mm Hg when compared to placebo (175). Phase 3
studies for NaltBup-SR (which included more than 3,000 patients) showed a modest additional
weight loss with this medication (approximately 4.5 kg, or 5% of initial body weight after one
year) and a direct correlation between weight loss and blood pressure reduction. However, among
patients losing more than 5% of initial body weight, the placebo-treated patients experienced a
larger fall in blood pressure than those on active treatment (close to an additional 4 mm Hg in
systolic and 2 mm Hg in diastolic blood pressure). Subjects on active treatment also exhibited a
slight increase in heart rate (additional 2–3 bpm) (176). This relative increment in blood pressure
and heart rate in the active group is likely attributable to the sympathomimetic effect of bupropion.
Clinical trials for injectable glucagon-like peptide-1 agonists have shown a small but sustained
reduction in body weight and systolic blood pressure (5.2 mm Hg) with this medication (227).
A beneficial effect is likely secondary to a combination of weight reduction and its effect on
extracellular volume and endogenous natriuretic peptides (223).
Bariatric surgery, which offers a substantially greater weight-loss effect than nonsurgical ther-
apies, also has a profound impact on blood pressure. The Swedish Obese Subjects (SOS) study

followed a cohort of more than 2,000 obese patients who underwent bariatric surgery [vertical
banded gastroplasty, 70%; (endoscopic) adjustable gastric banding (AGB), 24%; and RYGB, 5%)
and an equal number of matched controls (196). The authors observed that after two years, the
AGB: (endoscopic)
subjects who had undergone surgery lost on average 23.3% of initial body weight compared to adjustable gastric
a net gain of 0.1% in the control group. This weight change was associated with a significant banding
reduction of systolic (7 mm Hg) and diastolic (4.6 mm Hg) blood pressure. During this follow-up OR: odds ratio
period, normotensive subjects who had undergone bariatric surgery were less likely to develop
hypertension [24% versus 29%, odds ratio (OR) = 0.78, p = 0.06] than normotensive subjects
without surgery, and hypertensive subjects were more likely to achieve clinical remission of hy-
pertension (34% versus 21%, OR = 1.71, p < 0.001) as compared to untreated hypertensive
subjects (196). In the same study, a small group of participants who completed 10 years of follow-
up still had a significant weight reduction (16.1%) compared to controls (who gained 1.6%). At
that point, differences between groups in blood pressure, hypertension incidence, and remission
rates exhibited similar trends but didn’t reach statistical significance (196).
A recent meta-analysis by Chang et al. (33) that includes data from over 160,000 patients
enrolled in 164 studies (including RCTs and observational studies) estimates that all bariatric
surgical procedures together caused on average an additional 36.1 kg weight loss over two years.
The baseline overall prevalence of hypertension in this population was 47.4%, and bariatric surgery
was associated with a hypertension remission rate close to 75% over the same period of time (33).
In summary, weight loss is commonly associated with a clinically relevant reduction in blood
pressure, but the exact mechanism and long-term persistence of this effect remain unknown.
2.2. Coronary Artery Disease, Acute Coronary Syndromes,

and Stroke/Transient Ischemic Attack
The strong association between obesity and increased risk of acute coronary syndromes and stroke
has been extensively documented in large cross-sectional (245) and longitudinal (204) studies.
Despite the strong association between obesity and other cardiometabolic risk factors, a growing
body of evidence continues to support an independent effect of obesity in the development of major
cardiovascular events (234). Many epidemiological and retrospective studies have consistently
observed that the association between BMI and cardiovascular mortality has a U-shape, in which
subjects with either high or low BMI are at increased risk compared to individuals in the normal
BMI range (5). The interpretation of this observation, popularly known as the obesity paradox
(5), has been criticized by the retrospective nature of the data supporting it, the inability to assess
intentionality of weight loss, and the fact that the U-shape risk distribution disappears when
alternative anthropometric parameters to BMI [such as abdominal circumference (94) or lifetime
maximum weight (177)] are used to define obesity (52).
The Look AHEAD study, which included over 10 years of follow-up data, clearly documented
a significant improvement in cardiovascular risk factors but failed to find statistically and/or
clinically significant benefits of sustained weight loss on cardiovascular outcomes (237). Whether
these results are influenced by the characteristics of the participants, adverse effect of the
high-carbohydrate diet intervention, differences in the medications required for management of
cardiovascular risk factors, the modest long-term weight-loss effect of the active intervention (av-
erage 3.5% at 10 years) or the too-short length of follow-up continues to be an area of debate (237).
Two medications that were previously used to manage obesity have been withdrawn from the
market due to their association with adverse cardiovascular events (i.e., fenfluramine for inducing
valvular heart disease and sibutramine for increasing blood pressure and risk of nonfatal cardio-
vascular events) (37). The evidence supporting the long-term effect of the currently available

antiobesity medications on cardiovascular outcomes is very limited. Although orlistat has been on
the market for a few decades, there are no long-term studies reporting its effect on cardiovascular
events (191). Studies to determine the effect of some of the newer antiobesity medications on
T2DM: type 2
diabetes mellitus cardiovascular outcomes are planned (PhenTop-ER) or under way (NaltBup-SR) (226).
In a systemic review, Vest et al. (220) estimated that due to changes in cardiovascular risk
HR: hazard ratio
factors, subjects who undergo bariatric surgery reduce their overall 10-year coronary heart disease
IFG: impaired fasting
risk from 5.9% to 3.2% (estimations made by applying the Framingham Risk Score). Similarly, the
glucose
same authors reported that, among subjects without heart failure, other desirable cardiovascular
IGT: impaired
effects associated with bariatric surgery include reduction in left ventricular mass (an effect that
glucose tolerance
cannot be fully explained by changes in blood pressure) and improved diastolic function (in terms
of both E/A ratio and the left ventricle isovolumetric relaxation time); however, no changes in
ventricular volumes or ejection fractions were observed (220).
A more recent systematic review that included 14 observational studies with 29,208 patients
who had undergone bariatric surgery and 166,200 nonsurgical controls followed between 2 and
14.7 years (115) reported adjusted estimates that suggest a significant reduction in myocardial
infarctions among those who had undergone bariatric surgery compared to nonsurgical controls
(1.5% versus 3.1%, OR 0.58, 95% CI: 0.45–0.74). Similar beneficial effects were observed for
stroke (0.8% versus 1.3%, OR 0.63, 95% CI: 0.49–0.80) (115).
In summary, weight loss has been associated with improvements in cardiac morphology and
function as well as a reduction in cardiovascular risk factors and outcomes, but determining the
magnitude and duration of weight loss required to achieve such improvements remains an area of
active research.
3. EFFECT OF SUSTAINED WEIGHT LOSS ON DIABETES

AND GLUCOSE METABOLISM
The strong association between obesity and type 2 diabetes mellitus (T2DM) has been extensively
described in epidemiological and experimental studies (135). Overall, anthropometric parameters
such as BMI, waist circumference, and total body weight have all been identified as powerful
independent predictors of T2DM development (30, 32, 230). However, the relationship between
these anthropometric parameters and the risk of developing T2DM may not be linear, since
greater weight gain (≥20 kg) is associated with a disproportionally higher risk of developing
diabetes (63). Thus, among the general US adult population aged 30 to 55 years, the age-adjusted
yearly incidence rate of T2DM increased from 0.47% per year (among those weight stable ±5 kg)
to 1.17% per year [adjusted hazard ratio (HR) 2.66, 95% CI: 1.84–3.85] among those gaining 11
to 20 kg and up to 1.43% per year (adjusted HR 3.84, 95% CI: 2.04–7.22) for those gaining
more than 20 kg (63). The same study also suggests that approximately 27% of all new cases of
diabetes could be prevented by avoiding further weight gain in the adult population (regardless
of the initial body weight) (63). It is estimated that among those with modest weight gain, each
additional kilogram increases the risk of developing diabetes between 4.5% (63) and ∼9.0% (136)
over the following 10 to 20 years.
3.1. Weight Change and Risk of Developing Diabetes

in Individuals with Prediabetes
Prediabetes is a transitional stage between normal glucose homeostasis and T2DM. Criteria that
are commonly used to define prediabetes include impaired fasting glucose (IFG) and impaired
glucose tolerance (IGT). IFG is defined as fasting plasma glucose between 5.6 and 6.9 mmol/L
(as defined by the American Diabetes Association) (216) or between 6.1 and 6.9 mmol/L (as per

World Health Organization criteria). IGT is defined as a plasma glucose level between 7.8 and
11 mmol/L two hours after receiving an oral glucose load of 75 g. Subjects with IFG are at a higher
risk of developing T2DM, with an estimated yearly incidence close to 6% (141). The synergism
NNT: number
between obesity and these conditions in the future development of T2DM has been extensively needed to treat
documented (141).
The Diabetes Prevention Program (106) followed 3,234 subjects with IGT who were randomly
assigned to placebo, metformin, or lifestyle-modification interventions for up to four years (average
2.3 years) (106). The authors observed that lifestyle modifications were superior to metformin
and placebo in reducing body weight (4.0, 1.8, and 0 kg, respectively), as well as reducing the
development of T2DM (4.8, 7.8, and 11.0 cases per 100 person-years, respectively) (106). Similar
results were reported by the Finnish Diabetes Prevention Study (215), in which 522 obese subjects
with IFG were randomized to usual care or an intensive lifestyle intervention, with the latter
resulting in greater weight loss (0.8 versus 4.2 kg after one year, and 0.8 versus 3.5 kg after two
years), which was associated with a 78% reduction in the risk of developing T2DM (11% versus
23%) in the following 3.2 years [number needed to treat (NNT) = 8].
A previous systematic review that included nine RCTs and 5,168 patients with IGT showed
that behavioral interventions led to modest weight loss of 2 to 3 kg (approximately 3% of initial
body weight) after one and two years of follow-up, which is similar to the effect observed in
subjects with obesity who have normal glucose tolerance (143). In this review, the authors note
that the amount of sustained weight loss achieved was strongly correlated with the frequency
of intervention contacts performed during the same period of time (143). Three of the studies
included in this review reported the effect of such interventions on hemoglobin (Hb)A1c, which
was negligible over the first one to three years of follow-up. However, most studies consistently
showed a relative risk reduction in the development of T2DM close to 50% in the long term
(NNT fluctuating between 16 and 62) (143). Merlotti et al. (130) reported similar results in a
systematic review that included four RCTs that randomized approximately 3,000 obese subjects
with prediabetes to placebo or intensive behavioral interventions for weight management. In
this review, the authors estimated that the modest weight reduction associated with behavioral
interventions caused a substantial reduction in the risk of developing T2DM over the 3.8 years of
follow-up (OR 0.44, 95% CI: 0.36–0.52).
The XENDOS (XENical in the Prevention of Diabetes in Obese Subjects) study, which ran-
domized 694 obese patients with IGT, found that the addition of orlistat (120 mg three times
per day) to intensive lifestyle therapy results in a modest additional weight loss (5.8 versus 3.0 kg
for lifestyle alone) and a significant reduction in the annual incidence of T2DM (18.8% versus
28.8%, HR 0.551, 95% CI: 0.46–0.86; NNT = 10) after four years of follow-up (210). A sec-
ondary analysis of the SEQUEL study (71) shows that among a small subset of obese subjects with
prediabetes (approximately 180 individuals per group), treatment with PhenTop-ER (for up to
108 weeks) results in a dose-dependent weight-loss effect as high as 12.1% of initial body weight
(compared to 2.5% weight loss in those receiving placebo) that is associated with a 78.7% relative
reduction in the annual rate of progression to T2DM (1.3% versus 6.1%, p < 0.05; NNT = 21)
(71). Similar subanalyses for other antiobesity medications were not available upon the completion
of this review.
Assessing the effect of bariatric surgery on progression to T2DM among subjects with predia-
betes is rather challenging given that among patients eligible for bariatric surgery the prevalence
of diabetes is relatively high. A recent systematic review and meta-regression that included 3,650
patients participating in three large nonrandomized clinical trials identified only 166 subjects with
prediabetes (130). Despite the limited numbers, meta-regression analyses suggest that bariatric
surgery results in a substantial reduction in the progression to T2DM among high-risk subjects

(OR 0.1, 95% CI: 0.02–0.45) who undergo bariatric surgery. However, selection criteria differ-
ences make these comparisons difficult to interpret.
Overall, there is consistent evidence that in individuals with IFG, weight loss achieved by be-
havioral, pharmacological, and/or surgical interventions is associated with a substantial reduction
in progression to T2DM.
3.2. Effect of Sustained Weight Change in Individuals with Type 2

Diabetes Mellitus
Compared to nondiabetic subjects, those with T2DM are more likely to have obesity and less
likely to achieve an intentional and sustained weight loss or succeed in preventing further weight
gain using behavioral strategies for weight management.
Over the years, several experimental studies have evaluated the effect of intentional weight loss
on the management of diabetes. A meta-analysis that included 22 randomized trials of nonsurgical
and nonpharmacological interventions for weight management (4,659 subjects followed for one
to five years) concluded that the effects of such interventions on body weight is very modest (on
average −1.7 kg; 95% CI: 0.3 to 3.2 kg) and unlikely to have a significant impact on diabetes
remission rates (144).
More recently, the Look AHEAD study, which was specifically aimed at assessing the effect of
weight loss on T2DM management, showed that compared with controls, subjects who received
intensive behavioral therapy had a significantly greater weight loss (8.5% versus 0.5% of initial
body weight) and had a greater change in HbA1c (−0.65% versus −0.1%) after one year. Sim-
ilarly, in the intensive intervention group, a greater proportion of subjects had the prespecified
HbA1c target <7% (72% versus 50%); these subjects also had a greater reduction in medications
required for diabetes control (236). Four years later, subjects on intensive therapy had regained
approximately 50% of the initial weight loss but maintained a significantly higher weight loss
compared to those in the control group, who remained slightly below their baseline weight, and
there was little difference in glycemic control between the experimental groups (236).
Pharmacological interventions aimed at improving weight control have variable effects on glu-
cose homeostasis. A systematic review by Padwal et al. (152) showed that among those subjects with
established T2DM, orlistat therapy was associated with improved glycemic control [an additional
change in HbA1c of −0.24 (95% CI: −0.14 to −0.25%) and fasting plasma glucose −0.81 mmol/L
(95% CI: −0.30 to −1.33 mmol/L)].
All newer antiobesity oral agents have been tested in diabetic patients, but these studies have
generally excluded participants who require insulin. The BLOOM-DM (Behavioral Modification
and Lorcaserin for Obesity and Overweight Management in Diabetes Mellitus) study (146) ran-
domized over 294 patients to placebo or lorcaserin for 12 months. The active-treatment group
achieved an additional 3 kg weight loss compared to placebo (4.5 versus 1.5 kg, respectively);
this modest difference in weight change was associated with additional benefits on fasting serum
glucose levels (additional −0.86 mmol/l), fasting insulin levels (additional −9.72 ρmol/L), and ho-
meostasis model assessment index (additional −0.3), and a greater proportion of patients achieved
target HbA1c levels of ≤7% (50.4% versus 26.3%).
Effects of PhenTop-ER on diabetic populations were explored in two studies (OB-202/DM-
230 and CONQUER) (70) that included 215 subjects who received placebo and 239 who received
active treatment; the groups were followed for 56 weeks. The group on active treatment lost
significantly more weight (9.4% versus 2.7% of initial body weight), achieved a slightly greater
reduction in HbA1c (1.6% versus 1.2%), and was more likely to achieve the target HbA1c of <7%
(53% versus 40%) than the placebo-treated group (70).

The NaltBup-SR combination for obesity management in T2DM was tested in the Contrave
Obesity Research (COR)-Diabetes study (88), which randomized 505 patients in a 2:1 ratio and
followed them for 56 weeks. Compared with controls, subjects receiving active treatment achieved
HDL-C: high-density
a greater weight reduction (5.0% versus 1.8%) and a greater reduction in HbA1c (0.6% versus lipoprotein cholesterol
0.1%) and were more likely to reach the HbA1c target of <7% (44.1% versus 26.3%) (88).
TG: triglyceride
In every case, the magnitude of the effect attributable to weight loss itself (independent of
FFA: free fatty acid
other metabolic effects of these medications) is difficult to quantify given that participants were
also asked to change their dietary intake and increase their levels of physical activity.
Among the numerous beneficial effects of bariatric surgery, diabetes control is probably the
most extensively documented. The STAMPEDE (Surgical Therapy and Medications Potentially
Eradicate Diabetes Efficiently) study, for instance, is a small but elegant RCT that randomized
150 subjects with T2DM to medical therapy, medical therapy plus RYGB, or medical therapy plus
SG (103). After three years, the surgical groups (RYGB and SG) achieved a significantly greater
weight loss than controls (26.2 kg, 21.3 kg, and 4.3 kg, respectively) as well as a greater proportion
of patients with HbA1c <7% (65%, 65%, and 40%, respectively) and a greater proportion of
subjects who discontinued antidiabetic medications (58%, 33%, and 0%, respectively) (15).
A recent review by Chang et al. (33), which included approximately 10,000 diabetic patients
enrolled in 8 small RCTs and 43 observational studies, reported the effect of bariatric surgery on
diabetes control. These authors reported consistently high rates of diabetes remission in RCTs
(92%) as well as observational studies (86%), which seems remarkable when compared to the
observed remission rates in a small group of nonsurgical controls (17%) who received intensive
medical therapy (33). However, only a small proportion of these results (approximately 2%) origi-
nated from RCTs. Among different types of surgical techniques, RYGB seems to offer the greatest
benefit in terms of T2DM remission rates (estimated at 93%), followed by SG (85%) and LAGB
(68%) (33).
Overall, consistent data show that even modest weight loss will improve glycemic control in
patients with T2DM. In addition, a greater magnitude of weight loss, as can generally be achieved
only with surgery, may induce diabetes remission in a substantial proportion of patients.
4. EFFECT OF SUSTAINED WEIGHT LOSS ON LIPID HOMEOSTASIS

As with other cardiovascular risk factors, the mechanisms linking obesity and dyslipidemia are
complex. The classic lipidemic alterations typically associated with obesity include decreased high-
density lipoprotein cholesterol (HDL-C) and higher circulating levels of triglycerides (TGs), free
fatty acids (FFAs), small, dense low-density lipoproteins (LDLs), and apolipoprotein B. Dyslipi-
demia and insulin resistance are very close epiphenomena related to obesity. Insulin resistance
is known to induce hyperinsulinemic states that promote lipogenesis and increase production of
FFAs as well as TGs. Such plasma lipids, furthermore, can induce a state of insulin resistance in
peripheral tissues and perpetuate a dyslipidemia/insulin resistance vicious cycle (160).
A recent systematic review that included 18 trials assessing the effectiveness of nutritional
advice for weight management on several cardiovascular risk factors (3,044 patients; mean follow-
up 12 months) concluded that such interventions can result in a modest weight loss (less than 2 kg)
that is associated with a small but significant change in total cholesterol of −0.15 mmol/L (95%
CI: −0.23 to −0.06) and LDL cholesterol of −0.16 (95% CI: −0.24 to −0.08) but no effect on
TG or HDL cholesterol (166).
More complex lifestyle interventions for weight management leading to sustained weight loss
have shown a more beneficial effect on lipid profile. The Look AHEAD study, for instance, showed
that among subjects with T2DM, intensive behavioral therapy leading to an additional 5.3% loss of

initial body weight after four years was associated with a greater increase in HDL-C (0.095 versus
0.051 mmol/L, respectively) and larger reduction in TG (0.29 versus 0.22 mmol/L, respectively)
(237) in the intervention group compared to the control group. However, no differences between
the intervention groups were observed in the prevalence of dyslipidemia or the number of subjects
who required lipid-lowering medications (237). Previous studies have also shown that the beneficial
effect of diet-induced weight loss on lipid profile appears to be independent of the glycemic index
or the protein content of the diet (184) and that the benefits of behaviorally induced weight loss
on lipid profile may be absent in older subjects (greater than 60 years) (242).
All currently available pharmacological interventions for weight management have been tested
for their effects on lipid profile. In the case of orlistat, the modest weight loss caused by this
medication is associated with a reduction in both total cholesterol (−0.33, 95% CI: −0.20 to
−0.38 mmol/L) and LDL-C (−0.27, 95% CI: −0.22 to −0.31 mmol/L); equivocal or no effect on
TG; and, interestingly, a minimal but undesirable decrease in HDL-C (−0.02, 95% CI: −0.02 to
−0.04 mmol/L) (90).
Lorcaserin administration for weight management in nondiabetic subjects was associated with
a small decrease in TG (approximately −6% of baseline), no additional effect on LDL or TC, and
a relatively detrimental effect on HDL-C (when compared with placebo-treated subjects) (175,
176). Among subjects with diabetes, the use of lorcaserin was associated with a small beneficial
effect on both TG and HDL-C cholesterol but no effect on total or LDL-C. In most cases,
however, the effect on lipid profile appears to correlate with the amount of weight loss achieved
with the intervention (146).
PhenTop-ER had a greater effect on weight loss as well as a greater beneficial effect on all
lipid fractions, including an additional 3% reduction in TC, 3% to 5% reduction in LDL-C,
additional 15% reduction in TG, and additional 3% to 5% increase in HDL-C (176). Among
subjects with hypertriglyceridemia (>2.25 mmol/L at baseline), PhenTop-ER treatment resulted
in a 25% reduction in TG despite not having a proportionally larger effect on body weight (176).
Similar to other medications, the effect of NaltBup-SR on LDL cholesterol was variable across
studies; however, the benefit on other lipid fractions is consistent, including an additional 10%
reduction in TG and an increase of approximately 3 mg/dl in HDL cholesterol and a 40% to 50%
increase in the likelihood of improvement in HDL levels (compared to baseline) (176).
Surgical strategies for weight loss are also associated with a significant effect on lipid
metabolism. A systematic review by Courcoulas et al. (48) showed that both RYGB (n = 1,691)
and AGB (n = 588) resulted in adjusted remission rates for any dyslipidemia (62% and 26%,
respectively), hypertriglyceridemia (84% and 60%, respectively), and low HDL (86% and 66%,
respectively) after three years. Similar results were obtained by Chang et al. (33), who included
5 RCTs and 20 observational studies addressing this question and estimated a long-term dyslipi-
demia remission rate between 68% and 76% for all bariatric surgical procedures combined.
Overall, evidence supports behavioral, pharmacological, and/or surgical weight-loss associa-
tions with clinically relevant improvements in lipid profiles, predominantly by reducing TGs and
increasing HDL cholesterol. In contrast, the effects of weight loss on LDL cholesterol appear to
be less consistent.

GASTROINTESTINAL OUTCOMES
The importance of the gastrointestinal system in the pathophysiology and progression of
obesity-related comorbidities is well recognized. Epidemiological studies have shown that obesity
is associated with an increased risk of developing several gastrointestinal conditions, such as

gastroesophageal reflux disease, erosive esophagitis, hepatobiliary disease, and certain cancers
(particularly esophageal and gastric cancers). Among these conditions, nonalcoholic fatty liver
disease (NAFLD) and hepatobiliary diseases are particularly significant owing to their strong
NASH: nonalcoholic
association with increased body mass and the substantial impact of weight loss on their progression. steatohepatitis
5.1. Nonalcoholic Fatty Liver Disease

NAFLD includes a wide spectrum of liver histological changes, characterized by abnormal depo-
sition of fat, that are unrelated to alcohol consumption. Subjects with NAFLD are at greater risk
of progressing to nonalcoholic steatohepatitis (NASH) and developing hepatocellular carcinoma.
The pathophysiological mechanisms of this condition are not yet fully understood. However, a
strong association with obesity and other components of the metabolic syndrome has been well
established (182).
The overall prevalence of NAFLD is estimated to be approximately 30% for the general
population in Western communities; among subjects with obesity class 2 or greater, it is estimated
to be between 65% and 92%. Approximately one in four obese subjects with NAFLD also have
NASH (231).
Sustained weight loss and dietary interventions are considered the foundation for manage-
ment of NAFLD (55). Interestingly, even among normal-weight subjects (BMI 22 kg/m2 ), a small
(>3 kg) but sustained (>4 years) weight loss has been associated with a significant clinical im-
provement, including a 75% reduction in the prevalence of NAFLD and improvement in most
metabolic, hemodynamic, and liver function parameters (38).
Among subjects with excess weight, several behavioral interventions for weight loss have been
proposed to reduce liver steatosis and improve plasma markers of liver function (207). However,
the number of high-quality studies with follow-up periods greater than 12 months is limited. A
systematic review by Clark (42) identified two small observational studies and one nonrandomized
trial (n = 89) in which caloric restriction and exercise resulted in improved liver function and
steatosis, particularly among those achieving a sustained weight loss greater than 10% of initial
body weight. However, some evidence suggests that aggressive antiobesity interventions resulting
in very rapid weight loss (greater than 1.6 kg per week) may be associated with an undesirable
proinflammatory profile and further liver damage (55).
A subanalysis of the Look AHEAD study included 96 subjects in whom liver composition
assessments with proton magnetic resonance spectroscopy were performed periodically over a 12-
month period (121). The results from this subanalysis suggest that the group receiving intensive
therapy achieved a greater weight loss (8.5% versus 0.5%) and a greater decrease in liver steatosis
(51% versus 23% of baseline fat content). However, there were no significant differences in
aminotransferase levels between groups (121).
A recent review identified four small observational studies (total 59 subjects) that assessed the
effect of orlistat therapy on NAFLD (55). Overall, most reports suggested an improvement in liver
function and histology after six months of treatment. One small RCT published by Zelber-Sagi
et al. (247) randomized 52 obese subjects with NAFLD to orlistat or placebo plus diet and exercise.
After six months of treatment, both groups had a comparable weight loss, but the beneficial effects
of orlistat on glucose, lipids, and liver function parameters were substantially greater than the
effects of diet and exercise alone (247). The potential effects on NAFLD of newer antiobesity
agents have yet to be described.
The long-term effect of bariatric surgery on NASH has been reported in several studies,
including one by Dixon et al. (53), who found an 82% resolution of NASH after two years in their
study of 197 obese patients who had undergone LAGB. Similar results have been reported by a
number of authors and include studies with follow-up periods as long as five years (85).

A recent review by Hafeez & Ahmed (80) identified 12 small observational studies (total 576
subjects with obesity followed between 12 and 32 months) that assessed the long-term effects of
RYGB on NAFLD and liver steatosis using a combination of clinical and histological outcomes.
The authors observed that in every case, RYBG was associated with a significant improvement in
liver function. Complete regression of NAFLD ranged between 60% and 83%, and resolution of
liver fibrosis ranged between 35% and 50%. Interestingly, in five of those studies the authors also
reported incidental cases of worsening liver fibrosis after surgery (80).
Overall, NAFLD is commonly associated with excess weight and can show marked improve-
ment with behavioral, pharmacological, and/or surgical weight loss, whereas weight loss that is
too rapid may worsen liver histology in some patients.
5.2. Hepatobiliary Disease/Gallstones

Obese individuals have a significantly higher risk of having gallstones as well as presenting
with symptomatic gallstone diseases (23). Data from long-term cohort studies show that obese
men (76) and women (200) have a 2.5- and 3-fold increased risk, respectively, of presenting
with symptomatic gallstones. The estimated prevalence of gallstones among subjects with
severe obesity is close to 50% (6). Moreover, among subjects with obesity who had elective
cholecystectomy before gastric bypass surgery, the prevalence of gallbladder disease (including
cholecystitis, cholesterolosis, and cholelithiasis) can be as high as 95%, even though only 20% of
them present with sonographic findings prior to surgery (28). Previous epidemiological studies
have also described a correlation between higher BMI and increased prevalence of gallbladder
cancer, likely secondary to the higher prevalence of gallstones and the influence of other metabolic
alterations associated with obesity (246).
Interestingly, interventions that lead to rapid weight loss (greater than 1.5 kg/week) have
been associated with a greater risk of symptomatic cholelithiasis (189). This association has been
described with intensive behavioral interventions as well as with bariatric surgery (189). Between
28% and 71% of subjects who undergo bariatric surgery develop symptomatic gallstones (most of
them during the first six months after the procedure). In the first three years after surgery, as many
as one-third of patients require a cholecystectomy (205). The mechanisms by which weight loss
affects the pathogenesis of cholesterol gallstones are not fully understood, but the most commonly
proposed mechanisms include a greater cholesterol supersaturation of hepatic bile, a susceptibility
for precipitation of cholesterol crystal secondary to the presence of nucleation, and impaired
gallbladder motility leading to increased aggregation and growth of crystals into gallstones
(243).
Thus, not only is gallbladder disease common in patients presenting with obesity, but it is also
important to note that incidence and symptoms can increase with weight loss.
6. EFFECT OF SUSTAINED WEIGHT LOSS ON OSTEOARTHRITIS

AND CHRONIC PAIN
Obesity constitutes one the most relevant modifiable risk factors for the development of os-
teoarthritis (OA) (18). A recent meta-analysis that included 85 observational studies concluded
that obesity is associated with a nearly threefold increased risk of OA (OR 2.6, 95% CI: 2.3–3.1)
(18). Similarly, meta-analyses by Jiang and colleagues showed that every five-point increment in
BMI increases the risk of hip (96) and knee (97) joint OA by 11% and 35%, respectively.
Interventions leading to weight loss have been shown to be effective in reducing symptoms
in obese subjects with established knee OA. In a recent study, nutritional intervention leading

to weight loss >10% over four months resulted in a significant improvement in OA symptoms,
although there were no radiological signs of improvement (78). Similar results were reported in
an RCT by Bliddal et al. (20), who documented that a behavioral intervention that resulted in an
OSA: obstructive
additional 7% weight loss over one year (10.9 kg) compared to standard care (3.6 kg) was associated sleep apnea
with a significant long-term decrease in joint pain. Similarly, a meta-analysis by Christensen et al.
AHI: apnea hypopnea
(39), which included four RCTs with 454 patients randomized to standard care or behavioral index
weight-loss interventions, reported that a modest weight loss of 6.1 kg (5.1% of initial body
weight) was associated with a significant improvement in physical disability.
A recent systematic review by Groen et al. (77) identified 13 prospective studies (total 2,286 sub-
jects followed between three months and eight years) that assessed the effects of bariatric surgery
on knee pain and stiffness, physical function, and range of motion. Overall, 73% of all surgery
subjects reported a significant improvement in symptoms. Among those studies, the work by
Peltonen et al. (158) is the most prominent. Using the SOS database, the authors investigated the
two-year follow-up results from 1,203 surgical and 1,081 medically treated women and observed
that bariatric surgery (leading to loss of 27.6 kg versus 0.3 kg) was associated with a significantly
greater proportion of women reporting symptom improvement in all joints (ankle, 55% versus
21%; knee, 42% versus 21%; hip, 38% versus 21%; and back, 29% versus 18%) compared to med-
ically treated patients with no weight loss. Similar results were documented in a smaller sample of
men included in the study (158). Moreover, when data was pooled from all patients, the investi-
gators observed that the proportion of subjects presenting with work-restricting musculoskeletal
pain was inversely correlated with weight change.
In summary, obesity is widely recognized as a key modifiable risk factor for OA, with significant
improvements in pain and function reported with weight loss.
7. EFFECT OF SUSTAINED WEIGHT LOSS ON RESPIRATORY HEALTH

Obesity and respiratory health are closely related through complex and not fully elucidated mech-
anisms that include mechanical, inflammatory, and hemodynamic components. Over the past few
decades, the better understanding of the effects of hypoventilation syndromes on cardiovascular
health and quality of life, as well as the recent availability of new devices for ambulatory mon-
itoring, diagnosis, and management of sleep hypoventilation, has increased the awareness and
management of these common obesity-related comorbidities.
7.1. Obstructive Sleep Apnea

Obstructive sleep apnea (OSA) is a chronic condition characterized by a disturbed sleep pattern of
obstructive apneas, snoring, restlessness, or resuscitative snorts, and daytime sleepiness or fatigue.
The diagnosis and severity of OSA are defined by the average number of disordered breathing
events per hour [the apnea-hypopnea index (AHI)]. Typically, OSA syndrome is defined as an
AHI of 5 or greater with associated symptoms (excessive daytime sleepiness, fatigue, or impaired
cognition) or an AHI of 15 or greater, regardless of associated symptoms (156).
A recent population-based study documented that both men and women with obesity are more
likely to have OSA (63% and 22%, respectively) when compared with overweight subjects (21%
and 9%) or normal-weight peers (11% and 3%) (213). Individuals with OSA are at greater risk
of several cardiometabolic conditions, such as systemic hypertension, pulmonary arterial hyper-
tension, coronary artery disease, cardiac arrhythmias, heart failure, stroke, and diabetes, as well as
higher postoperative mortality and a two- to threefold increase in all-cause mortality (specifically
those with more severe cases) as compared with subjects without OSA (120).

Regardless of the strategy (behavioral, pharmacological, or surgical), intentional and sustained

weight loss has been associated with improvements in severity and, to a lesser extent, prevalence of
OSA. A small trial including 72 obese patients with mild OSA showed that compared with controls,
OHS: obesity
hypoventilation those receiving intensive nutrition and exercise counseling for one year achieved greater weight
syndrome loss (11 kg versus 2 kg) and reduction in the severity of the nocturnal respiratory symptoms,
with a mean AHI change from baseline of −4.0 versus 0.3 events per hour (214). Similarly, a
recent systematic review that included seven RCTs (total 519 subjects) concluded that behavioral
interventions caused a modest but significant decrease in the severity of OSA (change in AHI of
−6.0 events/hour compared to baseline). However, the effect of these interventions was not large
enough to significantly affect the prevalence of OSA (7).
In a systematic review of the impact of bariatric surgery on OSA, which included 13,900
participants from 69 different studies (including 3 RCTs), bariatric surgery resulted in an average
68.3% of excess weight loss and significant partial resolution (75%) or total resolution (30%) of
OSA (181). The authors also observed that biliopancreatic diversion was associated with a greater
benefit for OSA symptoms (99% improvement, 82.3% resolution), followed by laparoscopic SG
(72% improvement, 51% resolution), RYBG (73% improvement, 30% resolution), and LAGB
(70.5% improvement, 32% resolution) (181).
An RCT by Dixon et al. (54) randomized 60 patients with severe OSA (AHI average 61 ±
30 events/hour) to medical and surgical management. After two years, surgical patients with a
significantly greater weight loss (27.8 versus 5.1 kg) trended toward a greater reduction on the AHI
(−25.5 versus −14.0 events/hour, p = 0.16). The proportion of subjects achieving an AHI less than
15 (which is the cutoff point for mild OSA) was also higher in the surgical group (27% versus 7%);
however, only one patient in the control group achieved complete remission (54). Interestingly,
these authors also show that the relation between weight change and AHI is attenuated beyond
the first 10% or 10 kg of weight loss, due to great variability with greater weight changes.
Overall, OSA is a common complication of excess weight, and although weight loss can lead to
a clinically relevant improvement in AHI, complete resolution of OSA, even with surgical obesity
treatment, is not common.
7.2. Obesity Hypoventilation Syndrome

Obesity hypoventilation syndrome (OHS) is a clinical condition characterized by the triad of
obesity (BMI >30), daytime hypoventilation (PaO2 <70 mm Hg and PaCO2 >45 mm Hg), and
sleep-disordered breathing (AHI >5) without an alternative mechanical, metabolic, or neuromus-
cular condition that leads to hypoventilation (137). The key element that differentiates OHS from
OSA is the persistence of hypercapnia during daytime. It has been estimated that OHS affects 20%
of subjects with OSA and has a prevalence between 8% and 22% among bariatric surgery subjects
(35). This condition has been associated with a tenfold increased risk of developing cardiovascular
events and a greater short-term (18 months) mortality compared to BMI-matched normocapnic
controls (23% versus 9%, respectively) (35).
The magnitude of the correlation between BMI and the risk of OHS is not well established.
Some studies suggest that subjects with OHS tend to have a greater BMI than those with OSA
(104), whereas other reports suggest that BMI is not a good predictor of diurnal hypercapnia (105).
In one observational study that followed 690 subjects for four years, the authors observed that a
10% weight gain was associated with a 32% increase in the AHI, whereas a 10% weight loss was
associated with a 26% decrease in the AHI (159). A meta-analysis by Greenburg et al. (74), which
included 342 subjects (participating in 12 different trials), showed that the significant reduction
in body weight after bariatric surgery (leading to a BMI reduction from 55.3 to 37.7 kg/m2 ) was

associated with a 71% reduction in OHS severity as per the AHI (from 55 at baseline to 16 after
maximal weight loss was achieved). In 38% of subjects undergoing bariatric surgery, complete
resolution of OHS (defined as AHI <5) was documented 12 months after the surgical procedure.
COPD: chronic
Furthermore, bariatric surgery was associated with a significant long-term improvement in most obstructive pulmonary
parameters of pulmonary function such as PaO2 (53 mm Hg versus 73 mm Hg), PaCO2 (53 mm disease
Hg versus 44 mm Hg), forced expiratory volume in the first second (FEV1 ) (60% versus 80% of
predicted), and forced vital capacity (FVC) (84% versus 61% of predicted) (206).
In summary, OHS occurs in a significant proportion of patients with OSA, and substantial
weight loss may be required to alleviate it.
7.3. Chronic Obstructive Pulmonary Disease

The potential interactions between chronic obstructive pulmonary disease (COPD) and obesity are
not very well understood and could involve a number of pathophysiological mechanisms, includ-
ing impaired mechanical ventilation, increased production of proinflammatory adipocytokines,

dysfunctional and hypoxic adipose tissue, and impaired central ventilator control (64).
Multiple epidemiological studies have documented that the prevalence of obesity among sub-
jects with COPD is generally twice as high as in age/sex-matched subjects with no chromic
pulmonary disease (69). Interestingly, the prevalence of COPD among subjects with obesity has
been reported to be lower than in normal-weight subjects (44). In fact, among individuals with
severe COPD, those with greater obesity (more specifically, decreased fat free mass) have been
reported to have better long-term survival (183).
Nonintentional weight loss is a common complaint among COPD patients that has been associ-
ated with worse outcomes and has even been targeted as a therapeutic strategy (244). However, the
effect of orexigenic intervention in the long-term survival of COPD patients has never been tested
in controlled studies. It remains unclear whether the better long-term survival rate is an epiphe-
nomenon resulting from patient selection, an artifact caused by the specific effects of obesity on
pulmonary function tests, or a real protective effect of obesity in patients with severe COPD (64).
The specific effects of behavioral interventions for weight loss on patients with COPD have
not been addressed in a systematic way. Moreover, subjects with severe respiratory comorbidi-
ties have typically been excluded from RCTs of new antiobesity medications. Small cohort and
case-series studies have estimated that the prevalence of COPD among patients who undergo
bariatric surgery is approximately 23% (128); among a group of subjects with a diverse number
of respiratory comorbidities, bariatric surgery caused a significant improvement in FVC (82% to
115% of predicted), FEV1 (78% to 104% of predicted), arterial pO2 (75 mm Hg to 91 mm Hg),
and arterial pCO2 (44 mm Hg to 41 mm Hg) (128). Cremieux et al. (49) performed a secondary
analysis of the medical claims in a cohort of 5,502 individuals who had undergone bariatric surgery
and found that the proportion of subjects making at least one claim for COPD or other related
respiratory conditions (different from asthma and sleep disorders) decreased from 58% in the
3 months preceding surgery to 26% and 16% at 3 and 24 months after surgery, respectively.
Thus, despite an association between obesity and COPD, data on improved outcomes with
weight loss remain anecdotal rather than based on the results of prospective intervention trials.
7.4. Asthma
The association between obesity and asthma has been consistently established in several cross-
sectional and epidemiological studies (62). A large epidemiological study by Nystad et al. (145)
that included 135,000 Norwegians followed for over 20 years estimated that after adjusting for

multiple confounders, an increment in BMI of 1 kg/m2 above 20 kg/m2 in men and 22 kg/m2 in
women increases the risk of asthma by 10% and 7%, respectively. Similar findings have also been
reported in multiple cross-sectional studies (190) that show that obesity is consistently associated
with a two- to threefold increase in the prevalence of asthma. A large meta-analysis by Beuther &
Sutherland (14), which included more than 300,000 patients in seven different studies, reported
that compared with normal-weight subjects, overweight and obese individuals are 38% and 92%,
respectively, more likely to present with an incident case of asthma (14).
Small RCTs have shown that among subjects with obesity and stable asthma, behavioral inter-
ventions leading to a sustained body weight reduction of approximately 10 kg (10% of initial body
weight) are associated with a significant 7.6% improvement in lung function tests (both FVC and
FEV1 ) as well as significant improvement in symptom control and reduced need for asthma rescue
medication (1, 203). A recent systematic review by Moreira et al. (138), which included more than
300,000 subjects participating in 29 different studies, described a large variability in the reported
effect of weight loss on asthma prevalence and control (which precluded quantitative analyses).
However, the overall results suggest that sustained weight loss is associated with a significant
improvement in asthma symptoms, need for rescue medication, and frequency of exacerbations
(138).

FERTILITY/PREGNANCY
Several epidemiological studies have described the association between obesity and fertility prob-
lems. A large epidemiological study in American women showed that compared to women with
normal BMI, those who are overweight or obese have lower age-adjusted fecundity (OR 0.92 and
0.82, respectively) (72). Similar findings have been described in Danish (241) and African American
(240) women. In a prospective study that followed 500 obese women who had undergone in utero
insemination, the authors observed that having a larger waist-to-hip ratio (>0.8) was associated
with a 30% reduction in the chances of conception (168).
The mechanisms linking obesity and female fertility are still to be fully understood but may
include the inhibition of follicular maturation induced by hyperinsulinemia and hyperleptine-
mia and changes in the gonadotropin secretion pulses leading to changes in the ovulatory cycle
characterized by prolongation of the follicular phase and shortening of the luteal phase (219). In
women with polycystic ovary disease, for instance, obesity and anovulatory infertility are com-
monly concurrent problems (100). In this particular subgroup of patients, behavioral weight-loss
interventions that cause significant weight loss (16.2 kg over three months and 6.3 kg over six
months) have been associated with a significant rate of spontaneous ovulation (between 60% and
90%) (41, 79).
Obesity has also been associated with greater obstetric and miscarriage risk. A systematic review
by Boots & Stephenson (24) concluded that obesity itself confers a 31% greater risk of having a
miscarriage. Similar results were obtained by Metwally et al. (133), who completed a meta-analysis
of more than 16 observational studies and estimated that having a BMI over 25 kg/m2 increases
the risk of miscarriage by 67%. However, the authors of both reviews agreed that the results are
very heterogeneous among studies and highly variable among subgroups.
Some reports also suggest that obesity can affect fertility in men, but these results are less
consistent (239). Among men, intentional weight loss (either by behavioral or surgical means) has
been associated with a proportional increase in plasma levels of testosterone and gonadotropins
as well as a decrease in levels of estradiol (47). The beneficial effects of weight loss on several

endocrine parameters associated with subfertility such as leptin, interleukin-6, and plasminogen
activator inhibitor-1 have been extensively described, and in animal models, weight loss has been
shown to improve obesity-induced subfertility (111). Similarly, bariatric surgery is associated with
increased serum testosterone levels but paradoxically results in deterioration in sperm quality
(185). One small study suggested that there was no improvement in overall sexual function after
LAGB in males and that erectile index and orgasmic function worsened when adjusted for time
(164). The evidence supporting an effect of weight loss on the management of fertility issues is of
relative low quality, but the overall results suggest a benefit (192). Studies to evaluate the effect of
bariatric surgery on male fertility are needed (139).
A recent study by Johansson et al. (98) documented more than half a million pregnancies from
the Swedish Medical Birth Register records, including 670 that occurred in women who under-
went bariatric surgery before pregnancy. The authors found that compared with matched control
pregnancies, mothers undergoing prepregnancy bariatric surgery had lower risks of gestational
diabetes (1.9% versus 6.8%; OR 0.25; 95% CI: 0.13–0.47) or large-for-gestational-age infants
(8.6% versus 22.4%; OR 0.33; 95% CI: 0.24–0.44) but also had a higher risk of intrauterine
growth restriction (15.6% versus 7.6%; OR 2.2; 95% CI: 1.64–2.95) (98).
The effect of bariatric surgery on obstetric outcomes was evaluated in a systematic review by
Maggard et al. (127), who included 75 cohort studies and concluded that compared with obese
controls, pregnancies after bariatric surgery were less likely to present complications such as
gestational diabetes (0% versus 22.1%), preeclampsia (0% versus 3.1%), low birth weight (7.7%
versus 10.6%), and macrosomia (7.7% versus 14.6%). Nevertheless, female patients who undergo
bariatric surgery are generally advised not to become pregnant in the first 18 to 24 months
postsurgery.
9. EFFECT OF SUSTAINED WEIGHT LOSS ON URINARY

AND FECAL INCONTINENCE
Studies have shown weight loss to favorably impact both urinary and fecal incontinence. In a
study by Kuruba et al. (112) that included 201 patients who had undergone bariatric surgery,
the authors found that 65 (32%) of the subjects reported urinary incontinence before surgery; of
those, 82% reported improvement in urinary symptoms six months after the procedure. Others
have shown that the prevalence of urinary and fecal incontinence decreased after bariatric surgery
in 101 women (ages 20 to 55 years) with a BMI of 40 kg/m2 or more who underwent laparoscopic
RYGB and were followed for 6 and 12 months (26).
Surgically induced weight loss by LAGB has been shown to improve overall urinary incon-
tinence, quality of life, and stress incontinence in females but results in a worsening in urge
incontinence (164).
10. EFFECT OF SUSTAINED WEIGHT LOSS ON CANCER

PREVALENCE AND MORTALITY
A prospective epidemiologic study including more than 900,000 adults followed for 16 years
showed that men and women with a BMI greater than 40 kg/m2 had significantly higher death
rates from all cancers combined (RR 1.52, 95% CI: 1.1–2.1 for women and RR 1.62, 95% CI:
1.4–1.9 for men) (29). The association between obesity and cancer seems to be particularly strong
in certain types of cancer, including colon (116), renal, pancreatic, esophageal adenocarcinoma,
breast, and prostate (126). Interestingly, an inverse relationship with obesity has been described

for lung cancer and esophageal squamous cell carcinoma, and this association seems to persist
after adjusting for tobacco use patterns (122).
The dose-effect relationship between the degree of obesity and the risk of developing cancer
varies among malignancies but in most cases behaves in an exponential fashion (116). In endome-
trial cancer, for instance, the mortality risk ratio increases from 1.5 in overweight women to 2.5
and 6 in women with obesity class 1 and class 3, respectively (116).
Several recent studies have focused on the effect of intentional weight loss, especially the effect
of bariatric surgery, on cancer incidence (16), mortality (31), and recurrence (170). A prospective
follow-up study in more than 20,000 postmenopausal women who were initially free of cancer
suggests that intentional weight loss might reduce the risk of obesity-related cancers such as colon,
endometrial, and breast cancer (157).
Longitudinal studies from Canada (40), Sweden (195), and the United States (4) suggest that
there is a relationship between bariatric surgery and reduced cancer risk (129). McCawley et al.
(129) conducted a retrospective analysis of data for 1,482 women who underwent bariatric surgery
and 3,495 obese controls who received nonsurgical therapy. These authors observed that women
who underwent bariatric surgery had a lower incidence of cancer (3.6% versus 5.8%, p = 0.002)
and were younger at the time of cancer diagnosis (45.0 versus 56.8 years, p < 0.001) (31). A
Canadian study that followed 6,078 subjects between 1986 and 2002 showed that the incidence of
cancer was reduced by approximately 78% in subjects following bariatric surgery (40). Similarly,
the SOS study (with more than 2,000 surgical patients and an equal number of controls; average
follow-up 10.9 years) found that subjects who underwent bariatric surgery exhibited a 33% overall
reduction in the incidence of all cancers (HR 0.67, 95% CI: 0.53–0.85) (195).
Findings from a recent systematic review that included 13 studies assessing cancer mortality
after bariatric surgery (including four controlled studies) (31) suggest a significant reduction in
the risk of cancer death following bariatric surgery, with odds ratios ranging from 0.12 to 0.88
(31).
Another review identified 34 publications that reported intentional weight-loss data in relation
to cancer incidence or mortality. All studies except one were observational studies, the majority
used self-reported weights, and many did not define intentionality of weight loss (28 of the 34
studies) (16). Although 16 of the 34 studies found a significant inverse association between weight
change and cancer incidence or mortality, the remainder did not. The observed association was
more consistently seen in studies that investigated the effect of intentional weight loss (five of six
studies), and the risk reduction was greatest for obesity-related cancers and in women. This review
suggests that intentional weight loss results in a decreased incidence of cancer, particularly female
obesity-related cancers. However, there is a need for further evaluation of sustained intentional
weight loss in the obese, and studies need to rely less on self-reported weight data and have a
greater focus on male populations (16).
Potential mechanisms for the relationship between obesity and cancer have been proposed and
likely include endocrine-related changes due to excessive fat tissue (36). A review of studies on
the changes in cancer risk following intentional weight loss found that overall, estrogen levels
drop and sex hormone–binding globulin levels increase with intentional weight loss, whereas C-
reactive protein levels decrease substantially after weight loss (27). Reductions in tumor necrosis
factor-alpha and interleukin-6 are also consistently seen, but to a smaller magnitude, and after
weight loss there are small and inconsistent changes in insulin-like growth factor-I and insulin-like
growth factor–binding protein. The investigators suggested that because both cancer incidence
and levels of circulating cancer biomarkers drop fairly rapidly following weight loss, intentional
weight loss may well lead to meaningful reductions in cancer risk with a short latency time (27),
although data from randomized trials are not yet available to support this hypothesis.

11. EFFECT OF SUSTAINED WEIGHT LOSS ON MENTAL HEALTH

A greater prevalence of obesity among subjects with a diverse number of mental health issues (such
as depression, anxiety, bipolar disorder, and schizophrenia) has been extensively documented (125). BDI: Beck
In addition, many psychiatric conditions are associated with behaviors that promote weight gain Depression Inventory
and are often treated with medications known to induce weight gain (125).
Although mental health problems are highly prevalent in individuals living with obesity, the
long-term effects of sustained weight loss on mental health have not been examined or described
with the same rigor as other obesity-related health conditions. A number of instruments and scales,
most often focusing on depression, anxiety, self-esteem, and body image, have been used to assess
different mental health conditions among subjects achieving sustained weight loss.
A systematic review by Blaine et al. (19) included more than 4,500 subjects participating in more
than 117 different studies testing psychotherapy and pharmacological and surgical interventions for
weight management. The authors observed that the long-term effects of different interventions
on weight loss are highly variable depending on the type of intervention (2 kg weight loss for
psychotherapy and 30 kg for pharmacological/surgical interventions). In terms of depression, all

weight-loss interventions together had a positive impact on depression, with an average four-
point improvement in the Beck Depression Inventory (BDI) compared to baseline (19). When
analyzed separately, surgical and pharmacological interventions were associated with a greater
improvement in depression scales compared to psychotherapy interventions (with a change of
−5.0 versus −2.7 BDI points). The overall effect of a weight-loss intervention on self-esteem was
also positive but less pronounced than that observed for depression. In contrast to the findings for
depression, changes in self-esteem associated with weight loss were greater in the group receiving
psychotherapeutic interventions only, despite the fact that this group achieved a smaller weight
reduction than the pharmacological/surgical intervention groups (19).
A recent systematic review by Lasikiewicz et al. (117) addresses the question of whether
behavioral interventions for weight management can affect mental health outcomes. Although
the authors included 36 different studies in their analyses, few of those studies had observation
periods greater than 12 months (total 253 patients randomized to cognitive behavioral therapy
with diet or standard care). Overall, none of the studies demonstrated changes in self-esteem as
assessed by the BDI, the Rosenberg Self-Esteem Scale, or body image (using a variety of surrogate
measurements such as body dissatisfaction, appearance evaluation, and body shape concerns).
However, it may be worth noting that none of the experimental interventions have been shown to
have significant long-term effects on body weight, which makes such results difficult to interpret
(117).
A paradoxical association exists between weight loss following bariatric surgery and suicide
(161). One observational study that included 18,784 subjects followed for 38 years showed that
obese individuals have a higher risk of committing suicide (age-adjusted HR 2.2, 95% CI: 0.9–
5.3). They also observed that unexplained weight loss was associated with increased risk of suicide
regardless of body weight (HR 5.4, 95% CI: 2.3–12.5) (56). Because obesity is associated with
an increased risk of suicide (86), some researchers have suggested that the depression and suicide
ideation seen in some individuals following bariatric surgery may not be related to the surgery per
se (235), and depressive disorder may also persist in the bariatric surgery patient despite successful
surgical control of obesity (151).
Compared to pharmacological and surgical weight-loss interventions, behavioral interventions
leading to weight loss lack this association; however, in children and adolescents, unhealthy weight
loss through fasting, induced vomiting, or the use of laxatives has been associated with suicide
ideation and attempt (50).

Many mechanisms have been proposed for the association between long-term weight loss and
suicide. First, some pharmacological agents may affect centers of the brain that may lead to suicide
ideation, depression, and adverse effects. Other contributors may be the dissatisfaction with body
image that can follow dramatic weight loss, especially with the presence of loose redundant skin
(86), and alterations in metabolic biomarkers (134).
Windover et al. (235) found that the prevalence of past suicide attempts among bariatric patients
was greater than in the general population. Patients with a positive suicide history were significantly
likely to be younger, less educated, single, and female (235).
A US study found an increased risk of suicide after bariatric surgery (209). Compared with age-
and sex-matched suicide rates, there were substantially more suicides among patients who had
bariatric surgery during the 10 years following the procedure (209). The overall rate of successful
suicides in the bariatric surgical group was 6.6 per 10,000 (5.2 per 10,000 for female participants and
13.7 per 10,000 for male participants), which is significantly greater than the estimated incidence
of successful suicides for the general population (1.0 per 10,000) or the reported incidence in other
cohorts of obese patients who received nonsurgical management (0.9 per 10,000). Approximately
70% of the suicides occurred within the first three years following surgery. Similarly, a recent
systematic review of suicide mortality after bariatric surgery estimated that suicide rates in patients
are approximately 4.1 per 10,000 person-years (161).
Future studies on the relationship between long-term weight loss and suicide are needed,
especially in diverse populations, subgroups of patients, and individuals who engage in other long-
term weight-loss strategies apart from the use of antiobesity medications and bariatric surgery.
The potential relationship between failed weight-loss attempts and suicide ideation needs to be
evaluated. Subsequent studies should also adjust for confounders such as previous psychiatric
illness, medication/substance abuse, other abuses, and past suicide attempts. Caution may be in
order when considering bariatric surgery in patients with a history of suicide ideation or attempt.

ALL-CAUSE MORTALITY
There is ongoing controversy over the findings from epidemiological studies on the relationship
between weight loss and mortality. Contrary to the belief that weight loss should indirectly lead
to longevity through the overall improvement in cardiovascular risk profile, most of the evidence
from observational studies available at this point suggests that weight loss is associated with an
increase in both cardiovascular and all-cause mortality (83). In 2010, Ingram & Mussolino (93)
described a sample of more than 6,000 overweight and obese adults (>50 years of age) from the
Third National Health and Nutrition Examination Survey and observed that weight loss greater
than 15% of maximum body weight is associated with increased all-cause mortality. Simonsen et al.
(193) also reported that intentional weight loss of approximately 2 kg to 5 kg in overweight but
healthy individuals was associated with an increased risk of mortality. Similarly, a study on 4,869
men aged 56 to 75 years, with an observation window of 11 years, suggested that unintentional
weight-loss episodes of 20 or more pounds were associated with a 26% to 57% higher total
mortality risk in comparison with weight-stable peers (66).
However, these results are not completely reproducible, with some observational studies (107)
and RCTs [including an RCT in 585 subjects, with a mean age of 66 years, who were randomized
to behavioral weight-loss interventions; the follow-up period was 12 years (188)] documenting
neutral effects of weight loss on mortality. Some observational studies have also reported a benefit
of weight loss on mortality, including a prospective analysis with a 12-year follow-up of 4,970

overweight individuals with diabetes (40 to 64 years of age) that suggests intentional weight loss
by nonsurgical means is associated with substantial reductions in mortality (233).
The contradictory findings among epidemiological studies have been attributed to method-
ological issues surrounding the estimation of effect in the relationship between weight loss and
all-cause mortality, reverse causation, and adequate/overadjustment for confounding variables
such as smoking, sex (83), age, intentionality of weight loss, length of follow-up (75), presence of
comorbidity, and the initial weight status of subjects (187).
Data from controlled studies in this regard are very limited. The SOS study is the largest
controlled study with long-term follow-up in subjects undergoing substantial sustained weight loss
(albeit with surgery) (194). In a recent analysis, the authors reported that the mortality benefit of
bariatric surgery became evident after four to five years and continued to progress in the following
years. After 16 years, the adjusted mortality risk reduction was close to 30% (HR = 0.71, 95% CI:
0.54–0.92) for the surgical group compared to standard care (194).
13. EFFECT OF SUSTAINED WEIGHT LOSS ON QUALITY OF LIFE

Studies have shown that obesity (particularly morbid obesity) is associated with a decline in quality
of life (QOL) and may affect different dimensions of health-related quality of life (HRQOL)
(17). Using different HRQOL scales, several studies have generally also found that long-term
intentional weight loss may lead to improved QOL (110). The most commonly used measures
of HRQOL in adults are the Short Form 36 (SF-36), the Short Form 12 (SF-12), the EuroQol’s
EQ-5D, the Impact of Weight on Quality of Life-Lite (IWQOL-Lite), and the World Health
Organization Quality of Life Questionnaire (WHOQOL-BREF).
A sustained weight loss of >5% has been proposed to offer health benefits and an improvement
in HRQOL (91). In a four-year prospective cohort study of 40,098 US nurses ages 46 to 71 years,
Fine et al. (59) found that nurses with class 2/3 obesity who lost 20 pounds had a better physical
functioning profile. In an RCT involving 107 obese adults, a weight-loss intervention group with
dietary prescription, dietary counseling, and exercise showed improvements in physical fitness,
physical function, and overall QOL (221). Others have suggested that weight loss improves health-
related QOL only in obese individuals with obesity-related comorbidities but not in the so-called
metabolically healthy obese individuals (25). A recent large prospective study of women showed
a modest increase in scores of physical components of HRQOL related to weight lost (155).
However, other studies found that weight loss had a negative impact on physical function and
indices of HRQOL (95, 119). Interestingly, the beneficial effects of weight loss in overweight
and class 1 obesity remain controversial (81, 167). Furthermore, lack of satisfaction in patients
may impact HRQOL in patients following weight-loss intervention and may lead to inconsistent
findings.
Kolotkin et al. (108) found that prolonged weight management with combined phentermine-
fenfluramine and dietary counseling in 161 study participants (87.6% women) between 23 to
65 years of age, with a mean baseline BMI of 41 kg/m2 , led to a significant improvement in
HRQOL measured by IWQOL-Lite. Furthermore, they found that approximately 14% of the
variance in IWQOL-Lite total score could be accounted for by weight change. The authors also
noted that physical function and self-esteem were most strongly affected by weight loss (108).
Although it has been suggested that obese patients who undergo bariatric surgery have poor
psychological health (with a higher risk of suicide anxiety and depression) (161), most studies agree
that bariatric surgery offers a significant improvement in HRQOL (43, 87, 218).
An important consideration when interpreting QOL data is the minimal clinically important
difference (MCID) for each of the scales used. The MCID is the smallest change in score in any

domain of interest required for the patient to perceive a change in his/her life or to drive a change in
management. A recent paper by Warkentin et al. (229) challenged the common assumption that a
5% to 10% weight loss can produce a relevant change in QOL. Using data from a population-based
prospective Canadian cohort, the authors estimated that to achieve a clinically relevant change in
QOL, the minimal body weight reduction required ranged from 17% to 25%, depending on the
scale used to assess QOL (229).
In summary, the HRQOL of patients is an important clinical outcome, and weight loss should
not be the only aim of obesity management, although research does suggest that long-term weight
loss is associated with an improvement in HRQOL. Interest in the QOL of patients with obesity
continues to grow among researchers and clinicians, especially because of its clinical relevance and
the need for patients and health-care providers to decrease their focus on body weight, weight loss,
or other body composition measurements in isolation. Rather, patients and health-care providers
need to look at other beneficial health changes, such as an improvement in QOL, that may occur
as a result of a weight-loss intervention. Recent improvements in the quality of research on the
association between long-term weight loss and QOL are partly attributed to standardization of
QOL measures.
In order to strengthen the evidence that long-term weight loss may lead to an improvement in
HRQOL, more studies are needed, particularly RCTs that explore antiobesity drugs and effective
types of exercise, diet, and behavior. Future studies should include participants from different
populations (e.g., ethnic group, gender) and obesity subgroups. Reverse causation and temporality
are other methodological issues facing studies in this research area. Future follow-up studies should
also measure satisfaction in patients.
14. CONCLUSIONS AND OUTLOOK

Obesity is well recognized as a risk factor for a wide range of health issues affecting virtually
every organ system. There is now considerable evidence that intentional weight loss is associated
with clinically relevant benefits for the majority of these health issues. However, the degree of
weight loss that must be achieved and sustained to reap these benefits varies widely between
comorbidities. Downsides of weight loss that is too rapid and/or extreme may occur, as in the
increased risk of gallbladder disease, the presence of excess residual skin, or deterioration in liver
histology. Uncertainty also remains about the potential benefit or harm of intentional weight
loss on patients presenting with some chronic diseases and on overall mortality. Clearly, well-
controlled prospective studies are needed to better understand the natural history of obesity and
the impact of weight-management interventions on morbidity, quality of life, and mortality in
people living with obesity.
SUMMARY POINTS
1. Defining and assessing clinically relevant obesity and weight change are challenging tasks.
In a given individual, there is often little relationship between the magnitude of obesity
and measures of health.
2. Despite its modest effect on long-term weight loss, behavioral modifications that improve
eating behaviors and increase physical activity constitute a cornerstone for integral and
sustainable weight management.

3. Intentional weight loss is associated with a clinically relevant reduction in blood pressure,
improvement in cardiac function, and reduction in cardiovascular events. The duration
and magnitude of weight change required to achieve a significant benefit are still unclear.
4. In individuals with impaired glucose metabolism at any stage, intentional weight loss
achieved by any means is associated with a proportional reduction in T2DM prevalence,
severity, and progression.
5. Intentional weight loss is consistently associated with a clinically relevant reduction in
triglycerides and increase in HDL cholesterol. The effects of weight loss on LDL choles-
terol are less consistent.
6. Overall, nonalcoholic fatty liver disease is commonly associated with excess weight and
can show marked improvement with behavioral, pharmacological, and/or surgical weight
loss. Very rapid weight loss, however, may worsen liver histology in some patients. Simi-
larly, gallbladder disease is not only common in patients presenting with obesity but also
highly prevalent after intentional weight loss.

7. Obesity is widely recognized as a key modifiable risk factor for osteoarthritis, with sig-
nificant improvements in pain and function reported with weight loss.
8. Obstructive sleep apnea and obesity hypoventilation syndrome tend to improve with
moderate weight loss; however, complete resolution is not common and is related to
very significant weight loss.
9. Asthma and COPD are clearly associated with obesity. Sustained weight loss seems to
be associated with a significant improvement in asthma symptoms. Data for COPD are
rather limited.
10. Pregnant women who undergo bariatric surgery seem to be less likely to present obstetric
complications such as gestational diabetes, preeclampsia, and macrosomia.
11. Data on weight loss and suicide are controversial. Caution may be in order when con-
sidering bariatric surgery in patients with a history of suicide ideation or attempt.
12. Data suggest that long-term weight loss is associated with an improvement in health-
related quality of life. The amount of weight loss required to achieve a significant change,
however, remains controversial.
FUTURE ISSUES
1. The precise definition of success in terms of weight loss remains controversial, and
the dogmatic assumption that prolonged periods of sustained weight loss (greater than
10 years) are more likely than shorter periods to have a beneficial effect on health out-
comes has never been challenged.
2. Some evidence suggests that intentional weight loss may lead to meaningful reductions
in several conditions, such as COPD, and cancer risk with a short latency time, although
data from randomized trials are not yet available to support this hypothesis.

3. Future studies on the relationship between long-term weight loss and suicide are needed,
especially in diverse populations, subgroups of patients, and those who engage in other
long-term weight-loss strategies apart from the use of antiobesity medications and
bariatric surgery. The potential relationship between failed weight-loss attempts and
suicide ideation needs to be evaluated.
4. There is ongoing controversy over the findings from epidemiological studies on the
relationship between weight loss and mortality. Data from controlled studies in this
regard are very limited.
DISCLOSURE STATEMENT
A.M.S. has served as a paid consultant and speaker for makers of antiobesity medications and
devices, including Novo Nordisk, Takeda, Vivus, Orexigen, Zafgen, and Ethicon. C.F.R.C. and
A.A.O. are not aware of any affiliations, memberships, funding, or financial holdings that might
be perceived as affecting the objectivity of this review.
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NU35-FrontMatter ARI 18 June 2015 9:26
Annual Review of
Nutrition
Volume 35, 2015 Contents

Why Obesity?
George A. Bray p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 1
Direct and Functional Biomarkers of Vitamin B6 Status
Per Magne Ueland, Arve Ulvik, Luisa Rios-Avila, Øivind Midttun,
and Jesse F. Gregory p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p33
Manganese Is Essential for Neuronal Health

Kyle J. Horning, Samuel W. Caito, K. Grace Tipps, Aaron B. Bowman,
and Michael Aschner p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p71
Regulation of Selenium Metabolism and Transport
Raymond F. Burk and Kristina E. Hill p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 109
Vitamin E: A Role in Signal Transduction
Jean-Marc Zingg p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 135
CoQ10 Function and Role in Heart Failure and Ischemic
Heart Disease
Anita Ayer, Peter Macdonald, and Roland Stocker p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 175
Autophagy and Lipid Droplets in the Liver
Nuria Martinez-Lopez and Rajat Singh p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 215
Dietary Fatty Acids and Their Potential for Controlling Metabolic
Diseases Through Activation of FFA4/GPR120
Trond Ulven and Elisabeth Christiansen p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 239
New Insights into the Regulation of Chylomicron Production
Satya Dash, Changting Xiao, Cecilia Morgantini, and Gary F. Lewis p p p p p p p p p p p p p p p p p p 265
The Ontogeny of Brown Adipose Tissue
Michael E. Symonds, Mark Pope, and Helen Budge p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 295
The Roles of mTOR Complexes in Lipid Metabolism
Alexandre Caron, Denis Richard, and Mathieu Laplante p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 321
Use of Urine Biomarkers to Assess Sodium Intake:
Challenges and Opportunities
Mary E. Cogswell, Joyce Maalouf, Paul Elliott, Catherine M. Loria,
Sheena Patel, and Barbara A. Bowman p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 349
vi
NU35-FrontMatter ARI 18 June 2015 9:26
Glycemic Variability: Assessing Glycemia Differently and the

Implications for Dietary Management of Diabetes
Jeannie Tay, Campbell H. Thompson, and Grant D. Brinkworth p p p p p p p p p p p p p p p p p p p p p p p 389
Mediterranean Dietary Patterns and Cardiovascular Health
Jia Shen, Kobina A. Wilmot, Nima Ghasemzadeh, Daniel L. Molloy,
Gregory Burkman, Girum Mekonnen, Carolina M. Gongora, Arshed A. Quyyumi,
and Laurence S. Sperling p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 425
Itaconic Acid: The Surprising Role of an Industrial Compound
as a Mammalian Antimicrobial Metabolite
Thekla Cordes, Alessandro Michelucci, and Karsten Hiller p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 451
Health Benefits of Long-Term Weight-Loss Maintenance
Christian F. Rueda-Clausen, Ayodele A. Ogunleye, and Arya M. Sharma p p p p p p p p p p p p p p 475
Saturated Fats Versus Polyunsaturated Fats Versus Carbohydrates

for Cardiovascular Disease Prevention and Treatment
Patty W. Siri-Tarino, Sally Chiu, Nathalie Bergeron, and Ronald M. Krauss p p p p p p p p p 517
Regulation of the Epigenome by Vitamin C
Juan I. Young, Stephan Züchner, and Gaofeng Wang p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 545
Stable Isotope Ratios as Biomarkers of Diet for Health Research
Diane M. O’Brien p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 565
Indexes
Cumulative Index of Contributing Authors, Volumes 31–35 p p p p p p p p p p p p p p p p p p p p p p p p p p p 595

Cumulative Index of Article Titles, Volumes 31–35 p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 598
Errata
An online log of corrections to Annual Review of Nutrition articles may be found at

http://www.annualreviews.org/errata/nutr
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NU35CH16-Sharma ARI 6 June 2015 13:11

Annu. Rev. Nutr. 2015. 35:475–516 Keywords

The Annual Review of Nutrition is online at Abstract

AND GLUCOSE METABOLISM . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 488

3.1. Weight Change and Risk of Developing Diabetes

476 Rueda-Clausen · Ogunleye · Sharma

1.1. Assessing Patients with Obesity

www.annualreviews.org • Long-Term Weight Loss 477

Table 1 Parameters frequently used for the assessment of obesity

Parameter Measurement/estimation Obesity cutoff Advantage Limitations

Weight-to- = W (kg)/H (m) N/A Inexpensive, portable, Minimal validation

percent body Women:

ﬂoor at the level of the anterior superior Female from 80 to 90 cm

www.annualreviews.org • Long-Term Weight Loss

displacement the same principle as densitometry >35% women required equipment

1.2. Successful and Sustained Weight Loss Definition and Limitations

www.annualreviews.org • Long-Term Weight Loss 481

1.3. The Therapeutic Framework for Weight Loss

482 Rueda-Clausen · Ogunleye · Sharma

Sustained weight loss (kg)

Systolic BP (mmHg) Fasting glucose (% change)

Absolute change in proportion of subjects at A1c target (%)

www.annualreviews.org • Long-Term Weight Loss 483

1.4. Weight Management Beyond Weight Loss

484 Rueda-Clausen · Ogunleye · Sharma

2. EFFECT OF SUSTAINED WEIGHT LOSS ON MAJOR

www.annualreviews.org • Long-Term Weight Loss 485

486 Rueda-Clausen · Ogunleye · Sharma

2.2. Coronary Artery Disease, Acute Coronary Syndromes,

www.annualreviews.org • Long-Term Weight Loss 487

3. EFFECT OF SUSTAINED WEIGHT LOSS ON DIABETES

3.1. Weight Change and Risk of Developing Diabetes

488 Rueda-Clausen · Ogunleye · Sharma

www.annualreviews.org • Long-Term Weight Loss 489

3.2. Effect of Sustained Weight Change in Individuals with Type 2

490 Rueda-Clausen · Ogunleye · Sharma

4. EFFECT OF SUSTAINED WEIGHT LOSS ON LIPID HOMEOSTASIS

www.annualreviews.org • Long-Term Weight Loss 491

5. EFFECT OF SUSTAINED WEIGHT LOSS ON

492 Rueda-Clausen · Ogunleye · Sharma

5.1. Nonalcoholic Fatty Liver Disease

www.annualreviews.org • Long-Term Weight Loss 493

5.2. Hepatobiliary Disease/Gallstones

6. EFFECT OF SUSTAINED WEIGHT LOSS ON OSTEOARTHRITIS

494 Rueda-Clausen · Ogunleye · Sharma

7. EFFECT OF SUSTAINED WEIGHT LOSS ON RESPIRATORY HEALTH

7.1. Obstructive Sleep Apnea

www.annualreviews.org • Long-Term Weight Loss 495

Regardless of the strategy (behavioral, pharmacological, or surgical), intentional and sustained

7.2. Obesity Hypoventilation Syndrome

496 Rueda-Clausen · Ogunleye · Sharma

7.3. Chronic Obstructive Pulmonary Disease

ing impaired mechanical ventilation, increased production of proinﬂammatory adipocytokines,

www.annualreviews.org • Long-Term Weight Loss 497

8. EFFECT OF SUSTAINED WEIGHT LOSS ON

498 Rueda-Clausen · Ogunleye · Sharma

9. EFFECT OF SUSTAINED WEIGHT LOSS ON URINARY

10. EFFECT OF SUSTAINED WEIGHT LOSS ON CANCER

www.annualreviews.org • Long-Term Weight Loss 499

500 Rueda-Clausen · Ogunleye · Sharma

11. EFFECT OF SUSTAINED WEIGHT LOSS ON MENTAL HEALTH

psychotherapy and 30 kg for pharmacological/surgical interventions). In terms of depression, all

www.annualreviews.org • Long-Term Weight Loss 501

12. EFFECT OF SUSTAINED WEIGHT LOSS ON