The disease burden associated with obesity is substantial. Multiple confounders complicate

quantification of risk, not the least of which is variability in the degree of obesity itself, with increasing

BMI being associated with increasing risk of mortality and disease in a dose-dependent but nonlinear

fashion. Obesity is associated with decreased lifespan. Data from the Framingham Heart Study

demonstrate a loss of 3 and 6 years of life for overweight and obese men respectively,8 while NHANES

data demonstrate a loss of 13 years of life for severely obese men (BMI >45).9 Overweight and obesity

are associated with an increased risk of multiple diseases, among which type II diabetes is particularly

important. The association between obesity and diabetes is robust; relative risks for diabetes range from

2 to 15 for BMI in the overweight range and 20 to 90 for BMI in the obese range. The CDC estimates

that in the United States in 2011, the prevalence of type II diabetes was 8.3% among all adults and 27%

among those over 65 years of age. Furthermore, 35% of all US adults, and 50% of US adults over 65

years of age have elevated fasting blood glucose or HbA1c consistent with prediabetes. If current trends

persist, the prevalence of diabetes in the United States in 2050 will exceed 30%, and worldwide trends

parallel these US data.

Obesity is associated with an increased risk of multiple diseases, including atherosclerosis,

hypertension, hyperlipidemia, hepatic steatosis and steatohepatitis, sleep apnea, osteoarthritis,

gallbladder disease, endocrine disorders, autoimmune disease, allergy and atopy, multiple types of

cancer, and depression. Metabolic disease encompasses all of physiology. Risk ratios for overweight and

obesity-related diseases vary substantially depending on BMI, ranging from 2 to 5 for stage I obesity

with dramatic dose-dependent increases in risk with increasing BMI. For example, the prevalence of

hepatic steatosis in the general population is generally estimated to be approximately 30%, increases

progressively with increasing BMI, and exceeds 90% in obese patients with BMI >40. In the NHANES

population, the prevalence of sleep apnea was 3% in nonobese men and 12% in obese men (BMI

>30),10 but in a separate study of patients with severe obesity (BMI >40), prevalence exceeded 70%.11

This disease burden is associated with significant economic costs. While accurate quantification of

obesity-related healthcare costs is challenging and complicated by regional variability in payer systems

and patient demographics, a recent systematic review estimated that costs directly attributable to

overweight and obesity in the United States exceed 100 billion dollars annually and constitute 5% to

10% of total US healthcare spending.

MEDICAL MANAGEMENT

Treatment Strategies

The medical management of obesity falls into two primary categories: lifestyle intervention and

pharmacotherapy. Both strategies, with rare exceptions, achieve similar results, with modest weight loss

and high recidivism. Nonetheless, both strategies hold significant untapped promise, with advances

expected in coming decades, particularly in the areas of environmental engineering and

pharmacotherapy.

Lifestyle Interventions

3 Lifestyle interventions for obesity include any or all of three basic components: diet modification,

exercise, and psychological therapy. Interventions may be unsupervised or administered under the

supervision of clinicians, dieticians, or commercial weight loss plans, and may be individualized or

administered in group programs.

Diet modification is the mainstay of lifestyle intervention. Diet strategies vary with respect to

macronutrient composition, daily caloric intake, and food and caloric measurement methods, and

include low-carbohydrate diets, low-fat diets, meal replacement strategies, Mediterranean diets, very

low-calorie diets, and multiple commercial diet plans. No clear evidence demonstrates advantages of

any specific diet plan over others. Specifically, macronutrient composition does not impact on weight

loss when caloric intake is controlled – total calories, rather than the macronutrient composition of

those calories, is the variable that determines weight loss. In contrast to weight loss, conflicting

evidence exists regarding the role of macronutrient composition in improvement of metabolic disease,

with some evidence suggesting that low-carbohydrate diets (which include low-glycemic index–highfiber diets and very low-carbohydrate diets), when compared to low-fat diets, may be associated with

greater improvements in insulin resistance and triglyceride levels, and higher resting energy

expenditure. These studies must be interpreted with caution as follow-up is relatively short, and low1185

carbohydrate diets may be associated with adverse changes in low-density lipoprotein levels.12 Lowcarbohydrate diets also appear to provide better compliance than other diet strategies over short-term

follow-up of less than 6 months, but compliance differences vanish at follow-up exceeding 1 year.

Physical activity is a central component of lifestyle intervention for obesity. Exercise alone achieves

only modest weight loss, but exercise and diet potentiate each other. Importantly, exercise reduces

obesity-related mortality and cardiovascular disease risk independent of weight loss. Data regarding the

optimal type, duration, frequency, and intensity of exercise are conflicting and specific evidence-based

guidelines remain elusive. High intensity exercise may be more effective for weight loss, but many

obese patients are unable to engage in even moderate intensity exercise due to comorbid diseases such

as osteoarthritis. Increased daily nonexercise activities such as walking and stair use nonetheless may

provide modest weight loss and cardiovascular health benefits.

Of the wide range of psychological techniques used to treat obesity, cognitive-behavioral therapy is

most common. Cognitive-behavioral therapy achieves modest weight loss in the obese of approximately

2 to 3 kg at 1-year follow-up, with increased weight loss when combined with diet and/or exercise.

Increased frequency of psychological intervention and group therapy compared with individual therapy

are associated with greater weight loss.

Intensive lifestyle interventions are supervised multicomponent plans that involve a combination of

diet, exercise, and behavioral modification, with periodic monitoring by coaches and dieticians, and

individual or group psychological counseling. Two NIH-sponsored randomized controlled trials suggest

that intensive lifestyle interventions provide more durable results than standard lifestyle interventions,

although long-term outcomes of metabolic disease are conflicting. The Diabetes Prevention Program

randomized 3,234 overweight or obese insulin-resistant patients (mean BMI 34) to 1 of 3 experimental

arms: intensive lifestyle interventions, metformin treatment, or placebo treatment.13 After a mean

follow-up of 2.8 years, average weight loss in the intensive lifestyle interventions group was 5.6 kg

compared with 2.1 kg and 0.1 kg for the metformin and placebo groups respectively; at 10 years an

average weight loss of 2 kg was maintained in both intensive lifestyle interventions and metformin

arms relative to the placebo arm. The cumulative risk of incident diabetes was 34% lower in the

intensive lifestyle interventions arm and 18% lower in the metformin arm relative to the placebo arm.

The NIH-sponsored Look AHEAD (Action for Health in Diabetes) study randomized 5,145 overweight or

obese diabetic patients to a 4-year intensive lifestyle intervention involving diet and exercise

modification with regular on-site visits and counseling, or standard primary care provider-supervised

diabetes and weight loss education. After 8 years, mean weight loss was 4.7% and 2.1% in the intensive

lifestyle intervention and standard care arms respectively.14 Nonetheless, the study was halted after 11

years after no difference in cardiovascular events was observed. These studies demonstrate that while

modest, weight loss may be maintained over long periods with intensive lifestyle interventions,

although the effects on metabolic disease are equivocal. Of importance, in Look AHEAD, a subset of

patients in each arm (27% and 17% in intensive lifestyle intervention and standard care arms,

respectively), maintained a loss of >10% of total starting weight, suggesting that subpopulations of

patients are more responsive than others to lifestyle interventions, and that identification of predictors

of responsiveness would permit better allocation of care.

Assessing the overall efficacy of lifestyle interventions for obesity is challenging, as results vary

depending on the subgroup studied, follow-up is variable and often short, and program and outcome

reporting methods are widely disparate. The resultant complex body of literature limits our current

understanding of the efficacy of such interventions. Nonetheless, a preponderance of data suggests that

results of lifestyle interventions for obesity are modest, with mean weight loss between 2% and 10% of

total body weight over follow-up periods from 6 to 48 months. Unsupervised individual efforts

underperform more intensive, multicomponent, supervised, group interventions. Compliance is a critical

issue; individual diet programs are associated with attrition that may exceed 90% over a year or more

while attrition for intensive supervised efforts is less. Weight regain after program discontinuation is

common and long-term adherence to lifestyle changes is low. Despite these limitations, modest weight

loss, or exercise in the absence of weight loss, appears to have measurable if modest beneficial effects

on metabolic disease, with a subset of patients being responsive to such interventions. As such, lifestyle

interventions should be a component of the treatment of all obese patients, but only rarely achieve

dramatic and durable results.

Environmental Interventions – The Future

An understanding of importance of the interaction between environment and human genetics in the

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pathogenesis of obesity has shifted focus away from individual patient behavior modification and

toward manipulation of the obesogenic built environment. While rigorous data and proof of causality are

emerging, specific characteristics of the built environment have been linked to obesity, including

proximity and prevalence of fast food restaurants and full-service grocery stores, access to and quality

of exercise facilities, parks, and sidewalks, school and work environment food and exercise resources,

and public transit infrastructure. An emerging field of environmental and social engineering will shift

the focus of lifestyle intervention from individual to environment, and holds promise as next-generation

treatment for obesity.

Pharmacotherapy

4 The history of pharmacotherapy for obesity is replete with drugs that have been introduced with

much enthusiasm and variable efficacy but subsequently withdrawn due to unacceptable and in many

cases life-threatening side effects that became apparent only after widespread use. Sheep thyroid extract

was used in the late 19th century, while in the early 20th century, workers in the dye industry exposed

to 2, 4-dinitrophenol were observed to lose weight, leading to its use as a weight loss drug in the 1930s.

Amphetamines were popular weight loss drugs in the 1950–60s. All these agents were abandoned due to

prohibitive side effects. The modest efficacy of weight loss drugs is testament to the multiple redundant

physiologic systems that act to defend adipose tissue stores in the face of interventions designed to

reduce those stores. The frequent adverse effects of weight loss drugs speak to the interface between

body weight regulation and multiple fundamental physiologic processes, manipulation of which entails

substantial risk.

The largest and most important class of weight loss drugs targets monoamine signaling mediators

(norepinephrine, serotonin, dopamine, histamine) involved in CNS/hypothalamic control of satiety and

hunger. Many of these agents regulate multiple pathways and demonstrate overlapping activities.

Sympathomimetic agents that primarily potentiate norepinephrine release include phentermine,

introduced in 1959 and still in use today, and phenylpropanolamine, used as a decongestant and also as

a weight loss drug since the 1970s, but withdrawn from the market in 2000 after being associated with

an increased risk of stroke. Drugs that primarily potentiate serotonin activity include fenfluramine,

introduced in 1973 and withdrawn from the market in 1997, sibutramine (Meridia), a serotonin,

norepinephrine, and dopamine reuptake inhibitor with primary effects on serotonin and norepinephrine,

introduced in 1997 but withdrawn in 2010 after being linked to increased risks of myocardial infarction

and stroke, and lorcaserin (Belviq), a selective serotonin 2C agonist approved by the FDA in 2012.

Drugs that target dopamine signaling are currently being studied in clinical trials (e.g., bupropion,

tesofensine). Targeting multiple monoamine signaling pathways provides synergy. The combination

drug fenfluramine/phentermine (“Fen-phen”), introduced in 1992, demonstrated increased efficacy over

either agent alone, but was withdrawn from the market in 1997 after widespread use revealed serious

morbidity attributable to fenfluramine, including pulmonary hypertension and cardiac valvular disease.

In 2013, the FDA approved a combination drug of phentermine and topiramate, an antiepileptic with

multiple CNS activities (Qsymia). A combination formulation of bupropion and naltrexone, an opioid

antagonist which stimulates pro-opiomelanocortin neurons, is currently being studied in research trials.

Gut peptides have diverse metabolic functions including regulating satiety and hunger within the

hypothalamic feeding center, and include glucagon-like peptide 1 (GLP-1), cholecystokinin, ghrelin,

oxyntomodulin, pancreatic polypeptide, and amylin. Drugs based on these mediators show promise.

Many gut peptides have short biologic half-lives and research has focused on long-acting analogs or

mediators that target degradation pathways. GLP-1, secreted by ileal L cells in response to a meal,

induces satiety and potentiates insulin secretion and peripheral insulin sensitivity. Long-acting GLP-1

analogs, including liraglutide (Victoza) and exenatide (Byetta) are FDA approved for treatment of type

2 diabetes and are under investigation as primary weight loss agents.15 Ghrelin is so far the only known

orexigenic hormone, and ghrelin antagonists, agonists of ghrelin degradation pathways, and antighrelin

vaccines are in development. Amylin, released by pancreatic beta cells, induces satiety via CNS-based

mechanisms and also potentiates peripheral insulin resistance; pramlintide (Symlin), a human amylin

agonist, is approved for treatment of diabetes and induces modest weight loss. Orlistat (Xenical),

approved by FDA in 1999, is a pancreatic lipase inhibitor that blocks intestinal absorption of fat, and the

only drug to date that functions by reducing absorption of ingested calories. Side effects of orlistat

include diarrhea, steatorrhea, and increased risks of kidney stones and pancreatitis. Second-generation

lipase inhibitors are in development.

Agents designed to manipulate neuropeptide signaling within the hypothalamus, while not yet

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approved for use in humans, are important targets, and include drugs directed toward leptin,

melanocortin-4 receptor (MC4R), neuropeptide Y, and melanin-concentrating hormone. While leptin

resistance has confounded development of leptin as a therapeutic agent, recent data from animal models

suggest that concomitant treatment of endoplasmic reticulum stress may abrogate leptin resistance,16

while separate research demonstrates that amylin agonists also restore leptin sensitivity.17 These lines

of research have reinvigorated interest in leptin therapy. Mutations in the MC4R gene, a central

hypothalamic satiety mediator, are implicated in up to 5% of cases of common human obesity, and

MC4R agonists are currently in development. Other central-acting agents are directed toward

endocannabinoid signaling: rimonabant (Acomplia), a selective endocannabinoid antagonist, was denied

FDA approval in 2008 despite promising weight loss results in clinical trials due to an association with

depression and suicide, but interest in manipulation of endocannabinoid signaling persists.

Manipulation of thermogenesis and metabolic rate remains an active field of research. Thyroid

hormone achieves weight loss by increasing metabolic rate, but is associated with cardiac toxicity and

has detrimental effects on glucose homeostasis. Despite these failures, research persists. Many agents

discussed above that regulate food intake, most notably the sympathomimetics, also increase metabolic

rate, and it is unclear to what extent these effects contribute to weight loss. Agents that regulate steroid

metabolism, fatty acid oxidation and other aspects of adipose tissue, and skeletal muscle metabolism are

under study. Dietary constituents also regulate thermogenesis, including methylxanthines (e.g.,

caffeine), polyphenols (e.g., resveratrol, quercetin), capsaicinoids (found in chili peppers and mustards),

and medium-chain fatty acids, all of which represent potential therapeutic agents.

Overall efficacy of current obesity pharmacotherapy is modest, achieving weight loss of 3% to 10% of

total body weight. Most agents demonstrate synergy with lifestyle interventions. Current drugs

approved by the FDA specifically for weight loss include orlistat, the only drug approved for long-term

use; phentermine, approved for short-term use (<12 weeks) due to addiction potential and

cardiovascular toxicity; lorcaserin, FDA approved for use as an adjunct to lifestyle interventions; and

phentermine/topiramate. The XENDOS study (XENical in the Prevention of Diabetes in Obese Subjects)

randomized 3,305 patients to lifestyle intervention combined with either orlistat or placebo and at 4

years, and demonstrated a 5.8-kg weight loss in the orlistat arm compared with a 3.0-kg weight loss in

the placebo arm, as well as a reduced incidence of diabetes with orlistat therapy.18 Lorcaserin induced

5% weight loss compared with 3% in placebo-treated patients at 1 year.19 The phentermine/topiramate

combination drug achieved 10.5% weight loss compared with 1.8% in placebo-treated patients at 2-year

follow-up.20

A complete summary of obesity pharmacotherapy is beyond the scope of this chapter, which has by

necessity omitted important areas of research, including drugs that target steroid metabolism, lipid

metabolism, adipocyte differentiation and proliferation, and efforts to shift white adipose tissue toward

a brown adipose tissue phenotype (the “browning” of adipose tissue). This discussion has focused on

agents designed to treat obesity directly with the goal of weight loss, but an important parallel class of

drugs target metabolic disease independent of or in conjunction with weight loss. The activities of

weight loss drugs are complex and overlapping, with many agents regulating body weight and

metabolism via multiple mechanisms. Multiple redundancies in the regulation of energy homeostasis

suggest that drug combinations will enhance efficacy. As an understanding of these mechanisms

increases, safe and effective pharmacotherapy for obesity and metabolic disease will emerge.

SURGICAL MANAGEMENT

Bariatric Surgery – Beginnings

5 In contrast to lifestyle interventions and pharmacotherapy, surgical management of obesity is highly

efficacious. Modern bariatric surgery (Gr. baros, heavy, burden) is the result of over a half-century of

evolution in surgical technique that has its genesis in the 1940–50s with experiments in animals and

isolated operations in humans that employed small intestinal resection and jejunocolic and ileocolic

bypasses of various anatomic configurations. These operations involved substantial morbidity and did

not achieve widespread acceptance, but set the stage for development of the jejunoileal bypass, the first

bariatric operation to be widely applied in humans. Jejunoileal bypass involved division of the jejunum

14 inches distal to the ligament of Treitz and creation of a jejunoileostomy 4 inches proximal to the

ileocecal valve, and was thus referred to as a “14–4 bypass” (Fig. 46-1). In 1969, Payne and Dewind21

published the first report describing long-term clinical outcomes in a large group of patients who

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