Obesity: Scope, Lifestyle Interventions, and

Medical Management
Benjamin J. McCafferty, BS,* James O. Hill, PhD,† and Andrew J. Gunn, MDz

Obesity is a public health epidemic in the United States, with implications for patients across
many organ systems. Despite improvements in understanding the pathophysiology and increas-
ing number of therapies for obesity, its prevalence continues to rise. The purpose of this review
is to provide the interventional radiologist with an understanding of (1) the epidemiology of obe-
sity; (2) the impact of obesity on patients and the healthcare system; (3) the causes of obesity;
(4) conservative management of obesity; and (5) pharmacologic management of obesity.
Tech Vasc Interventional Rad 23:100653 © 2020 Elsevier Inc. All rights reserved.

KEYWORDS Obesity, diet, physical activity, pharmacology for obesity

Introduction adiposity in excess. Yet, the measurement of adiposity proves

difficult. Multiple metrics exist to help quantify obesity. The

O besity is a public health epidemic in the United States

(US), with implications for patients across many organ
systems.1-17 Despite improvements in understanding the
most common of these, body mass index (BMI), is a useful
surrogate for adiposity and obesity.22 BMI is calculated by
dividing an individual’s weight in kilograms by their height
pathophysiology and increasing number of therapies for obe- in meters squared (kg/m2). Three primary categories exist for
sity, its prevalence continues to rise.18-20 The purpose of this BMI measurements: normal (<25 kg/m2), overweight (25-29
review is to provide the interventional radiologist with an kg/m2), and obese (>30 kg/m2). Obesity can be further
understanding of (1) the epidemiology of obesity; (2) the divided into classes I (30-34.9 kg/m2), II (35-39.9 kg/m2),
impact of obesity on patients and the healthcare system; (3) and III (> 40 kg/m2).22 A review of »900,000 patients in 57
the causes of obesity; (4) conservative management of obe- prospective studies found the lowest all-cause mortality was
sity; and (5) pharmacologic management of obesity. associated with a BMI of 22.5-25 kg/m2.23 This “optimal”
BMI is often used as a target for individuals in weight loss
programs or in estimating one’s “ideal weight”. This same
review also highlights the utility of BMI as a surrogate mea-
Epidemiology of Obesity sure for the negative effects of adiposity.23 For example, after
Measures of Obesity excluding the first 5 years of follow-up, each increase of
Obesity is a chronic, multifactorial disease that involves more 5 kg/m2 above 25 kg/m2 increases overall mortality by 30%.
than simply over-eating.21 Obesity itself is straightforward: Type II diabetes mellitus (T2DM) is the highest specific cause
of mortality in this cohort, and is most severe in obese indi-
*University of Alabama at Birmingham School of Medicine, Birmingham, AL. viduals. Nonetheless, BMI is not a direct measure of adiposity
y
Department of Nutrition Sciences, University of Alabama at Birmingham, and, as such, can be misleading in high fitness, cachectic, or
Birmingham, AL. high-fat/low-mass individuals.23,24
z
Division of Vascular and Interventional Radiology, Department of Even though BMI is the most widely employed measure of
Radiology, University of Alabama at Birmingham, Birmingham, AL.
obesity, others do exist. For instance, increases in waist circum-
Funding: This manuscript was not supported by any funding.
Conflict of Interest: None of the authors report a potential conflict of interest ference are associated with increased mortality, even at a normal
associated with this work and there is no grant support associated with BMI.25 In one study, every 5 cm increase in waist circumference
this work. above normal increases mortality by 17% for men and by 13%
Address reprint requests to Andrew J. Gunn, MD, 619 19th St S, NHB for women.26 Another study has found that the highest waist
H623, Birmingham, AL 35249. E-mail: [email protected]

1089-2516/14/$-see front matter © 2020 Elsevier Inc. All rights reserved. 1

https://doi.org/10.1016/j.tvir.2020.100653
2 B.J. McCafferty et al.

circumferences decrease life expectancy by 3 years in men and by Impact on Patient Health
5 years in women when compared to individuals with smaller Obesity has significant implications for a patient’s health,
waist circumferences.25 When used in conjunction with BMI, including an association with T2DM and cancer.1-9 The preva-
waist circumference can be useful for distinguishing elevated lence of T2DM so closely mirrors the increases seen in obesity
BMI due to high muscle content rather than increased adiposity. that they have been labeled “twin epidemics”.1 In this regard,
For instance, a high BMI but low waist circumference would be 61.3% and 87.5% of adults diagnosed with diabetes are either
more suggestive of high muscle density, rather than a high BMI obese or overweight, respectively.2 Two hormones thought to
and high waist circumference. Apart from waist sizing, classic be involved are useful for illustrating how T2DM and obesity
skinfold thickness measurements have shown a similar ability to can be linked.3-5 Tumor necrosis factor alpha, an inflamma-
predict overall mortality.27,28 More advanced methods of mea- tory mediator, is increased in obese patients, but also acts to
suring obesity include magnetic resonance imaging (MRI) of total reduce insulin sensitivity, thereby preventing glucose
adipose tissue and dual-energy X-ray absorptiometry.27 These uptake.3,4 Adiponectin is an insulin-sensitizer that is reduced
methods can accurately quantify adipose tissue, but come at the in both patients with obesity and T2DM.3,5 Although these
expense of time and financial cost. Thus, they are less commonly hormones are critical for insulin desensitization and are altered
used in clinical practice. in obesity, they should not be considered definitive cause-and-
effect players of T2DM and obesity. The link between T2DM
and obesity is a complex topic that has not been fully eluci-
Epidemiology dated. Apart from T2DM, obesity has been shown to be associ-
Historical and future trends in obesity’s prevalence in the US are ated with various forms of cancer via hormonal, inflammatory,
illustrated in Figure 1. Currently, there are 93.3 million obese and otherwise unknown mechanisms.6,7 Indeed, weight,
adults in the US, which represents 39.8% of adults.18,19 More- weight gain, and obesity have been estimated to be responsible
over, 68% of the population is either overweight or obese.18,19 for »20% and »14% of all cancer deaths in women and men,
By 2030, obesity is predicted to increase in prevalence by respectively.6,7 Additionally, increases in BMI have been linked
another 33%, and severe obesity by 130%.20 Regionally, the to higher rates of thyroid, colon, endometrial, gallbladder,
southern US has a higher proportion of individuals with obesity renal, and esophageal cancer.8,9 Finally, a BMI of ≥40 kg/m2
as Alabama, Arkansas, Louisiana, Mississippi, and Oklahoma all increases the overall mortality of a cancer patient by 52%-62%
have a prevalence of ≥35%.18 Comparatively, the western US when compared to cancer patients with a normal BMI.7 Yet,
uniformly has less people with obesity, being led by Colorado the deleterious effects of obesity are not limited to T2DM and
that has a prevalence of <20%.18 In fact, all contiguous states cancer. Obesity imparts an increased risk of several other dis-
west of Colorado have a prevalence of <30%.18 In addition to eases including: obstructive sleep apnea10, hypertension11,12,
regional differences, racial differences in obesity exist, and are cardiovascular disease such as myocardial infarction and
summarized in Figure 2. In short, non-Hispanic Blacks (46.8%) stroke13-15, and dyslipidemia.16 Adipose tissue secretes such
and Hispanics (47%) self-report the highest incidences of obe- significant amounts of immunoregulatory mediators like
sity, while Asian-Americans self-report the lowest (12.7%).18 tumor necrosis factor alpha and interleukin-6 (IL-6) that obe-
Increases in the prevalence of obesity over the last 30 years have sity itself is considered an inflammatory state in the body.17
affected Americans of all racial backgrounds, with a 16.1% Lastly, there are psychosocial consequences to obesity, includ-
increase among non-Hispanic Blacks, 18.6% increase among ing an association with other psychiatric disorders and social
Hispanics, and 16.3% increase among non-Hispanic Whites.18 stigmas observed in children as young as pre-school age.29-31

Figure 1 US prevalence of BMI categories. Data not available for normal and overweight BMI 2030 predictions. Adapted
from: National Center for Health Statistics. Health, United States, 2017 & Obesity and severe obesity forecasts through 2030.
Obesity 3

Figure 2 US prevalence of obesity by race. Note: total Hispanic data were not recorded until 2007, thus only Hispanics
of Mexican origin were included. Asian American data were not recorded until 2013, and was not included in this
figure. Adapted from: National Center for Health Statistics. Health, United States, 2017.

Impact on Healthcare Expenditures significant role in the development of obesity. A large major-
The estimated annual medical cost of obesity is $85.7 billion, ity (86%) of Americans are not meeting recommended daily
with prescription drug spending as the major expense.32 If physical activity levels.40 The decline in physical activity has
individuals who are overweight are included, the cost of been attributed to several factors.40 First, work-related activ-
greater-than-normal BMI becomes $209.7 billion annually.33 ity has been reduced due to a decline in participation in
In other terms, 21% of national healthcare expenditures in high-activity occupations like agriculture and construction.
the US are used for obesity-related illnesses.33 Overall, indi- Second, the widespread use of automobiles and public trans-
viduals with obesity spend 42% more on healthcare than portation has lessened the need for physical activity required
normal weight individuals.32,33 In the absence of obesity, for daily commutes or errands. Finally, there has been an
Medicare and Medicaid spending would be 8.5% and 11.8% overall increase in sedentary activities like viewing television
lower, respectively.32 In the workforce, obesity costs $8.65 or watching movies.40
billion per year in lost productivity.34 Severely obese employ-
ees cost employers more than double that of normal weight
employees.35 However, the financial impact of obesity goes Hormonal Regulation of Metabolism
beyond obesity alone. Specifically, an increase in patients Even though caloric imbalances are an important focus for
with obesity has ties to an increase in patients with T2DM. physicians working with patients to lose weight, the hormonal
The total costs of caring for patients with T2DM are esti- regulation of metabolic homeostasis should not be ignored.
mated to be $327 billion annually, a 26% increase since The following section will outline the key hormonal regulators
2012.36 In 2017, T2DM alone cost the US $90 billion in of metabolism, which are also summarized in Table 1. These
reduced productivity.36,37 Patients with diabetes have medi- hormones are current and potential targets of pharmacologic
cal costs that are more than 2-fold higher than individuals management, but have lasting impacts on the biology and
without diabetes.36,37 behavior of the patient attempting to reduce their weight.
Adiponectin is an insulin-sensitivity regulator secreted by
adipocytes.5,41,42 Adiponectin levels are reduced in both
patients with obesity and T2DM due to decreased hepatic
Causes of Obesity expression of adiponectin receptors.3,5,41 Of note, weight loss
Diet and Physical Activity significantly increases levels of adiponectin.5 Adiponectin can
In its simplest form, obesity is energy intake in excess of suppress hepatic gluconeogenesis independent of insulin
energy expenditure. Diet and physical activity patterns are
impacted by biology, behavior, and environment. While the
Table 1 Summary of the Major Hormones Involved in
clinician has some ability to change biology and behavior,
Metabolic Homeostasis. Ghrelin is the Only Known Hunger-
there has been little success in altering the patient’s environ- Stimulating Hormone
ment. Experience has shown that few people can achieve
Hunger Satiety
energy balance at a healthy weight in today’s environment.
Although the composition of the American diet has not dra- Ghrelin Adiponectin*
matically changed since 1970, the number of calories con- CCK
sumed has increased.38,39 Currently, the average person in Leptin
the US consumes 3800 kcal/day, despite guidelines that PYY
advise a 1600-3000 kcal/day diet to maintain caloric bal- GLP-1*
ance.38 Energy expenditure, or lack thereof, also plays a *Insulin sensitizer.
4 B.J. McCafferty et al.

levels.41 Adiponectin leads to activation of the endogenous dominant blood supply to the gastric fundus. These efforts
insulin-sensitizing agents, adenosine monophosphate depen- and their results are outlined in other articles in this issue.
dent kinase and peroxisome proliferator activated receptor
a.5,41,42 Overall, adiponectin leads to a total body sensitization
to insulin without altering the circulating amount of insulin.41
Cholecystokinin (CCK) is the prototypical satiety hor- Conservative Management of
mone, although it is not dramatically altered by obesity.43 Obesity
Secreted by I cells in the small intestine in response to food
within the small bowel, CCK functions to decrease food The term “lifestyle management” is often used to describe
intake. Through neural and endocrine mechanisms, CCK is weight loss therapies that do not require medications, proce-
believed to delay gastric emptying and evoke satiation cen- dures, or surgeries.54 According to the National Institutes of
trally.43 The administration of exogenous CCK been unsuc- Health, there are 3 main components to lifestyle manage-
cessful an anti-obesity target due to its short half-life.43 ment: dietary interventions, physical activity interventions,
Leptin is a long-term mediator of satiety, with blood levels and behavioral modification.55 It is also helpful to think of
correlating to the amount of body fat.44,45 Leptin acts on the treatment in 2 parts: a weight loss phase and a weight loss
hypothalamus via a Janus kinase signal transducer and acti- maintenance phase. It is common for patients to succeed in
vator of transcription pathway to suppress appetite, reduce losing weight initially, but few succeed in keeping it off long
body weight/fat, and decrease glucose.5,44 Exogenous leptin term. Food restriction is the key to the weight loss phase.
has demonstrated no significant benefits when administered Although patients can lose weight with exercise alone, it typi-
to patients with obesity, suggesting a state of leptin resistance cally requires more than most people can be reasonably
in obesity.41,45,46 expected to do over the long term. However, with weight
Peptide YY (PYY) is produced within intestinal L cells in loss maintenance, physical activity becomes the best predic-
response to food in the small bowel, and acts at neural and tor of success. In short, diet is the critical component for los-
gastrointestinal levels to reduce food intake and encourage ing weight, but physical activity is the critical key for keeping
satiety.47 PYY, similar to leptin, stimulates hypothalamic sati- weight off. For quantifying success, a reduction of as little as
ety centers while simultaneously delaying gastric emptying.43 5% of the initial body weight is considered clinically signifi-
PYY levels are reduced in obesity, resulting in poor post- cant, and leads to improvements in blood sugar, blood pres-
prandial appetite control.47 Unlike leptin, the exogenous sure, and hyperlipidemia.54
administration of PYY can activate satiety pathways, making
it a potential pharmacologic target.47
Glucagon like peptide 1 (GLP-1) is co-secreted with PYY
Dietary Interventions
by L cells of the small intestine in response to high fat and When counseling patients, emphasis should be upon lower-
carbohydrate meals.48 GLP-1 induces satiety in 2 ways. First, ing caloric intake to produce a 500 kcal/day deficit. This sim-
it delays gastric emptying by binding to parietal cells and ple intervention can be quite effective, as trials have shown
downregulating vagal stimulation of the stomach.48 Second, that low calorie diets induce a 7%-10% weight loss within 6
it suppresses appetite by acting on receptors within the months of initiation.56 With this is mind, current guidelines
brainstem.48 Additionally, GLP-1 promotes insulin secretion, for dietary intake of macronutrients recommend that 45%-
and can even increase glucose sensitivity.48,49 The combined 65% come from carbohydrates, 20%-35% from fat, and
effects of GLP-1 on insulin, glucose metabolism, and satiety 10%-35% from protein.57 Most popular diets vary these
have made it an intriguing pharmacologic target for both parameters to achieve a weight loss effect. For example, the
obesity and T2DM. This will be further discussed in the highly effective Mediterranean diet consists of 50%-55% car-
“Medical Management of Obesity” section. bohydrates, 30% fat, and 15%-20% protein while prioritizing
Ghrelin is the only known orexigenic or hunger-stimulat- fruits, vegetables, healthy fats, nuts, and fish.57 Low carbohy-
ing hormone.50 Ghrelin is predominately synthesized in the drate diets suggest 35% carbohydrates, 45% fat, and 15%
gastric fundus, although it is produced in other locations as protein.57 Low fat diets, where fat intake is reduced by 10%
well.50 Ghrelin receptors are found in the appetite control and protein intake is increased to 25%, have been shown to
centers of the central nervous system.50,51 The hypothalamic satiate patients using fewer overall calories.58,59 Despite these
and dorsal vagal complex locations assist in actual appetite findings, no specific plan has shown to be more effective so
control, while mesolimbic dopaminergic ghrelin receptors long as an energy intake deficit occurs.54 With regards to
play a role in the reward pathway of eating.50,51 Intuitively, food content (eg, low vs high fat), weight loss trumps any
ghrelin is increased during fasting, which contributes to the negative effects of individual dietary components.
difficulty of hypocaloric dieting for weight loss. Paradoxi-
cally, ghrelin is lower in obese individuals, but it fails to be
suppressed properly following meals when compared to nor- Physical Activity Interventions
mal-BMI individuals.52,53 Given its unique function in the The American Heart Association recommends that patients
body, ghrelin has been a target for both pharmacologic and engage in 200-300 minutes/week of high-level physical activ-
interventional radiology therapies for obesity. Interventional ity for weight loss, and at least 150 minutes/week of moderate
radiologists have targeted the production of ghrelin to induce physical activity to prevent weight gain.54,60 The beneficial
weight loss through embolization of the left gastric artery, the effects of exercise differ depending on their duration and
Obesity 5

intensity. Longer, higher-intensity activities promote weight loss for obesity is through behavioral changes in patient energy
attenuation to a greater degree.60 Care should be taken to intake and expenditure.
increase physical activity gradually with realistic milestones
and goal progressions. Aerobic exercise without the benefit of
dietary modifications only achieves a 3%-5% weight loss in Lipase Inhibitors
patients with obesity.61 Orlistat [Xenical, Genentech, San Francisco, CA] was the first
anti-obesity agent approved in the US to exert full effects in
the gastrointestinal tract rather than the central nervous sys-
tem. It functions by irreversibly binding and inhibiting the
Behavioral Modifications
active serine site on pancreatic and gastric lipases. Inhibition
Behavioral interventions may be the least understood aspect of prevents the absorption of approximately one-third of dietary
lifestyle management for clinicians, since it is driven primarily fats.67 Average weight loss with lipase inhibitors is 2.5-
by psychologists and dietitians who help the patient with 3.5 kg, while 35%-73% of patients achieve clinically signifi-
coaching, eating pattern modifications, and motivational inter- cant weight loss.68 79% of patients experience gastrointesti-
viewing. Yet, physician involvement is crucial for patients. nal adverse effects; namely, flatus with discharge (40.1%),
When controlling for demographic and weight status, patients oily spotting (32.7%), and fecal urgency (29.7%).67 Other
receiving weight loss advice from a healthcare professional are non-gastrointestinal adverse events include liver failure and
3 times more likely to desire weight loss, and at nearly 4 times nephropathy.68 The clinical utility of orlistat is limited by the
greater odds of trying to lose weight.62,63 Clinically significant need to take the drug 3 times per day, and the relatively high
weight loss is also more likely in overweight and obese patients rate of mild to moderate gastrointestinal side effects.67
if their physician had told them they were overweight in the
past year.64 The Centers for Disease Control and Prevention
offers a 3-step approach to behavioral modifications consisting Selective Serotonin Receptor Agonists
of reflection, replacing, and reinforcement.65 Reflection encour-
Lorcaserin [Belviq, Eisai, Woodcliff Lake, NJ] is a selective
ages individuals to keep a food diary to track eating habits and
agonist of specific serotonin (5HT) receptors.69 Lorcaserin
uncover cues for eating. Replacing involves changing the habits
activates 5HT2C receptors to stimulate the release of a-mela-
identified during reflection, such as eating more slowly or plan- nocortin, a hypothalamic hormone that decreases appetite
ning meals ahead of time. Reinforcement is for motivating indi-
and energy intake.69 Average weight loss is 3.2 kg, and 38%-
viduals and promoting patience with the new lifestyle.65
48% of patients experience clinically significant weight
loss.68 Common adverse drug reactions include headache
(14.5%-16.8%), dizziness (7%-8.5%), nausea (8.3%-9.4%),
and dry mouth (5.3%).70 Serious but less common adverse
Medical Management of Obesity effects of lorcaserin include bradycardia (0.3%), cognitive
Pharmacologic intervention for patients with obesity is indi- disturbances (2.4%), serotonin syndrome (1.7%), depressant
cated for individuals with a BMI of >30 kg/m2, or ≥27 kg/m2 effect (10.2%), and cardiac valvopathy (2.5-2.9%).68,69
with obesity-related comorbidities.66 Table 2 summarizes cur-
rently available drugs for obesity, which are discussed in detail
below. Typically, pharmacotherapy is discontinued if the Sympathomimetic Amine Anorectic/
patient does not lose ≥5% of the starting body weight within Antiepileptic Combination
3 months.66 Although pharmacologic management of obesity Phentermine-topiramate [Qsymia, Vivus Inc, Campbell, CA]
provides treatment options to the physician, it warrants reiter- is a central nervous system-targeted drug approved for
ation that the most effective and sustained method of weight weight loss in 2012.71 Phentermine causes a release of

Table 2 Summary of Medications Used for Weight Loss

Weight Patients with
Drug Mechanism Loss (kg) ≥ 5% Weight Loss Adverse Effects Complications

Orlistat Lipase inhibitor 2.5-3.5 35%-73% Gastrointestinal (GI) Liver failure,

disturbances nephropathy
Lorcaserin 5-HT agonist 3.2 38%-48% Headache, dizziness, dry Serotonin syndrome,
mouth, nausea depressant effects
Phentermine- Sympathomimetic 6.7-8.9 45%-70% Paresthesia, dizziness, GI Teratogenic, cardiovas-
topiramate and antiepileptic disturbances cular events
Naltrexone- Opioid antagonist 2.0-4.1 36%-57% Nausea, headache, dizzi- Seizure risk, avoid in
bupropion and antidepressant ness, GI disturbances alcohol and drug
abusers
Liraglutide GLP-1 agonist 5.9 51%-73% Nausea, headache, hypo- Pancreatitis, suicidality,
glycemia, GI disturban- thyroid cancer, renal
ces, fatigue failure
6 B.J. McCafferty et al.

norepinephrine, as well as acting as a minor dopamine- and Conclusion

5HT-releasing agent.72 This increase in sympathetic nervous
In summary, obesity is a chronic, multifaceted disease epi-
system activity decreases appetite via downregulation of
demic that is best managed through lifestyle changes, which
vagus nerve activity. Topiramate is a commonly used anti-
can be complemented by pharmacologic treatments.
epileptic that modulates the release of an inhibitory neuro-
transmitter, g-aminobutyric acid (GABA), but its role in
weight loss in poorly understood.71 Average weight loss is
6.7-8.9 kg, with clinical success in 45%-70% of patients.68 References
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