Obesity

Goals of the lecture

1. Explain the underlying causes of overweight and obesity.

2. Identify parameters used to diagnose obesity.

3. Identify desired therapeutic goals for patients who are

overweight or obese.

4. Recommend appropriate nonpharmacologic and pharmacologic

therapeutic interventions for overweight or obese patients.

5. Educate patients about the disease state and associated risks,

appropriate lifestyle modifications, drug therapy, and surgical

options necessary for effective treatment

Introduction

Overweight and obesity are terms used to describe weight

measurements greater than what is considered healthy for a given

height. Body mass index (BMI), waist circumference,

comorbidities, and readiness to lose weight are used in the

assessment of overweight or obese patients. The primary modality

in defining overweight and obesity is the BMI. BMI does not

reflect distribution of body fat; therefore, the measurement of

waist circumference is a more practical method to evaluate

abdominal fat before and during weight loss treatment

ETIOLOGY

Obesity occurs when there is increased energy storage

resulting from an imbalance between energy intake and

energy expenditure over time. The specific etiology for

this imbalance in the vast majority of individuals is

multifactorial, with genetic and environmental factors

contributing to various degrees. In a small minority of

individuals, excess weight may be attributed to an

underlying medical condition or an unintended effect of a

medication.

Genetic Influences

Observational studies in humans and experimental

studies in animal models have demonstrated the strong

role of genetics in determining both obesity and

distribution of body fat. In some individuals, genetic

factors are the primary determinants of obesity, whereas

in others, obesity may be caused primarily by

environmental factors. The genetic contribution to the

actual variance in body mass index (BMI) and body fat

distribution is estimated to be up to 80%.

Environmental Factors

Many of the societal changes

associated with economic

development over the past 40 years

have been implicated as potential

causes for the increase in the

prevalence of obesity. These include

an abundant and easily accessible

food supply and the material

comforts of modern life, which have

contributed to a reduction in physical

activity.

Medical Conditions

Conditions associated with weight gain include

iatrogenic and idiopathic Cushing’s syndrome, growth

hormone deficiency, insulinoma, leptin deficiency, and

various psychiatric disorders, such as depression, binge-

eating disorder, and schizophrenia. Hypothyroidism is

often included in this list, but it mostly causes fluid

retention (myxedema) and is generally not a cause of

significant obesity.

Medications

An increasing number of medications are associated with

unintended weight gain. These include several

anticonvulsants (e.g., carbamazepine, gabapentin,

pregabalin, and valproic acid), antidepressants (e.g.,

mirtazapine and tricyclic antidepressants), atypical

antipsychotics (e.g., clozapine, olanzapine, quetiapine,

and risperidone), conventional antipsychotics (e.g.,

haloperidol), and hormones (e.g., corticosteroids, insulin,

and medroxyprogesterone). Although the pharmacologic

mechanism responsible for weight gain is usually drug-

specific, in most cases the precise mechanism is

unknown.

PATHOPHYSIOLOGY

Although a correlation between body weight in parents and

children exists, the specific gene or genes contributing to

obesity are unknown. The key factor in the development of

overweight and obesity is the imbalance that occurs between

energy intake and energy expenditure. The extent of obesity

is determined by the length of time this imbalance has been

present. Energy intake is affected by environmental

influences, including social, behavioral, and cultural factors,

whereas genetic composition and metabolism affect energy

expenditure

PATHOPHYSIOLOGY

Energy Intake

Food intake is regulated by various receptor systems. Direct

stimulation of serotonin 1A subtype (5-HT1A) and

noradrenergic α2-receptors increases food intake, serotonin

2C subtype (5-HT2C) and noradrenergic α1- or β2-receptor

activation decreases food intake. Stimulation of histamine

receptor subtypes 1 and 3 and dopamine receptors 1 and 2

results in lower food consumption. In addition to receptor-

modulated food consumption, higher levels of the protein

leptin are associated with decreased food intake. In contrast,

elevated levels of neuropeptide Y increase food intake.

PATHOPHYSIOLOGY

Energy Expenditure

A person’s metabolic rate is the primary determinant of

energy expenditure. The metabolic rate is enhanced after

food consumption and is directly related to the amount and

type. Physical inactivity may predispose an individual to

overweight and obesity. In addition, endocrine-related

disorders (e.g., hypothyroidism and Cushing’s syndrome)

may lower the metabolic rate, further contributing to the

development of overweight and obesity.

DIAGNOSIS

The parameters that use to determine obesity involve,

•BMI

•waist circumference

•The presence of comorbidities or associated risks.

The presence of comorbidities

The presence of comorbidities: (CHD, atherosclerosis, type

2 diabetes mellitus, and sleep apnea) and cardiovascular

risk factors (cigarette smoking, hypertension, elevated low-

density lipoprotein cholesterol, low high-density

lipoprotein cholesterol, impaired fasting glucose, family

historyof premature CHD, and age) requires identification

and aggressive management for overall effective treatment

of the overweight or obese patient

TREATMENT

Desired Outcome

The treatment goals for overweight and obesity are to

prevent additional weight gain, reduce and maintain a

lower body weight, and control related risks. Specific

weight goals should be established that are consistent with

medical needs and the patient’s personal desire.

Weight loss is indicated for patients with a BMI of 25 to

29.9 kg/m2 or an elevated waist circumference with two or

more comorbidities or for any patient with a BMI of 30

kg/m2 or greater.

If weight loss has been achieved and/or maintained for 6

months, therapy promoting further weight loss may be

considered.

TREATMENT

General Approach to Treatment

1. Before recommending any therapy, presence of

secondary causes of obesity (medical conditions or

medication) must evaluate.

2. If no secondary cause exists, the presence of other

cardiovascular risk factors and comorbidities must be

determined to guide clinical decisions

3. Treatment of obesity includes:

Lifestyle changes (dietary modification, enhanced

physical activity, and behavioral therapy)

pharmacologic treatment

surgical intervention

Or a combination of modalities.

TREATMENT

Nonpharmacologic Therapy

Nonpharmacologic therapy, including reduced caloric

intake, increased physical activity, and behavioral

modification, is the mainstay of obesity management. This

combination is recommended as first-line therapy

Reduced Caloric Intake

Current adult guidelines recommend reduced caloric

intake through adherence to a low-calorie diet (LCD). The

LCD should provide restricts daily calories to a range of

1000 to 1200 kcal for women weighing less than 75 kg and

1,400 to 1,600 kcal for all others.

TREATMENT

Nonpharmacologic Therapy

Exercise

Although diet and exercise contribute to weight loss,

combining an LCD with physical activity results in greater

weight loss compared with either therapy alone. In

addition, physical activity can help to prevent weight

regain and reduce related cardiovascular risks. Slow

titration of both the amount and intensity of physical

activity is recommended for most overweight and obese

patients. A program that incorporates daily walking is a

viable option for most patients.

Pharmacologic Therapy

Pharmacotherapy is not recommended for individuals

with BMIs of less than 27 kg/m2. If lifestyle changes do

not result in a 10% weight loss after 6 months, drug

therapy in addition to a healthy lifestyle is warranted for

overweight individuals with other related risks and for

obese patients.

Pharmacotherapy in addition to lifestyle modification is

reserved for patients with a BMI of 30 kg/m2 or greater,

or a BMI of 27 kg/m2 or greater with other obesity-

related risk factors.

Pharmacologic products promoting weight loss are

classified according to their mechanisms of action,

including the suppression of appetite and the

suppression of fat absorption

Pharmacologic Therapy

Because obesity-related risks resurface with weight

regain, long-term treatment is recommended to minimize

these sequelae.

Prolonged use of both fenfluramine and dexfenfluramine

monotherapy and fenfluramine and phentermine in

combination resulted in cardiac valvular disease.

Long-term treatment with sibutramine resulted in an

increased risk for nonfatal heart attacks and nonfatal

strokes in patients with preexisting cardiovascular

disease.

Therefore, orlistat is the only drug currently approved

for long-term use in promoting weight loss and

preventing weight regain.

Orlistat

Mechanism of action: Orlistat promotes and maintains

weight loss by acting locally in the GI tract. Orlistat is a

chemically synthesized derivative of lipstatin, a natural

product of Streptomyces toxytricini that inhibits

pancreatic and gastric lipases, as well as triglyceride

hydrolysis. As a result, undigested triglycerides are not

absorbed, causing a caloric deficit and weight loss.

Dose: Initiate orlistat 120 mg three times a day. Orlistat

may be taken during or up to 1 hour after the meal. Doses

above 360 mg/day provide no greater benefit and thus are

not recommended

Orlistat

Adverse effect: Common adverse reactions observed were

fatty or oily stools, oily spotting, oily evacuation, or abdominal

pain and/or flatulence with bowel movements. Soft stools,

nausea, increased defecation, and fecal incontinence also were

noted.

Interactions

Orlistat reduces the absorption of some fat-soluble vitamins

and β-carotene.

Hypothyroidism has been observed in patients taking both

orlistat and levothyroxine.

Administration of orlistat in conjunction with cyclosporine

can result in decreased cyclosporine plasma levels

Orlistat is contraindicated in patients with chronic

malabsorption syndrome or cholestasis

Sibutramine

Sibutramine and its two active metabolites (M1 and M2)

induce weight loss by inhibiting the reuptake of serotonin,

norepinephrine, and dopamine. Appetite becomes

suppressed because patients feel a sense of satiety. Because

an increased risk for nonfatal myocardial infarction (MI)

and nonfatal stroke was observed for sibutramine-treated

patients, FDA withdraws sibutramine from the U.S.

Phentermine

Mechanism of actions: Phentermine decreases food intake,

and hence weight, by increasing norepinephrine and

dopamine release in the central nervous system (CNS).

Uses: This drug is indicated for short-term use—no more

than a few

Doses In conjunction with a healthy lifestyle, 30 to 37.5 mg

of phentermine is administered once daily, typically before

breakfast or 1 to 2 hours after the morning meal; some

patients may be managed adequately at 15 to 18.75

mg/day, but a dose of 18.75 mg twice daily may be used to

minimize side effects, excluding insomnia.

Phentermine

Adverse reactions: Common adverse reactions seen with

phentermine use include heart palpitations, tachycardia,

elevated blood pressure, stimulation, restlessness, dizziness,

insomnia, euphoria, dysphoria, tremor, headache, dry

mouth, constipation, and diarrhea.

Contraindication:

Phentermine should be avoided in patients with unstable

cardiac status, hypertension, hyperthyroidism, agitated

states, or glaucoma. Phentermine use should be avoided in

patients concomitantly receiving or having received a

monoamine oxidase inhibitor (MAOI) within the preceding

14 days. Because phentermine is related to the

amphetamines, the potential for abuse is high

Diethylpropion

This sympathomimetic amine exudes similar

pharmacologic activity as the amphetamines, resulting in

CNS stimulation and appetite suppression.

Doses: Diethylpropion is available as both an immediate-

and a controlled-release product. In conjunction with a

reduced calorie diet and/or exercise, dose diethylpropion

(immediate release) 25 mg three times a day before meals

or 75 mg (controlled release) once a day, usually

midmorning

Adverse effect:

Use of diethylpropion for a period longer than 3

months is associated with an increased risk for

development of pulmonary hypertension.

common CNS adverse effects included

overstimulation, restlessness, dizziness, insomnia,

euphoria, dysphoria, tremor, nervousness, drowsiness,

mydriasis, and blurred vision. In addition, diethylpropion

can decrease the seizure threshold, subsequently increasing

a patient’s risk for an epileptic event.

Other organ systems also can adversely be affected,

resulting in tachycardia, elevated blood pressure,

palpitations, dry mouth, GIT disturbance, impotence or

change in libido, gynecomastia, and bone marrow

suppression.

Contraindications:

Patients with pulmonary hypertension, advanced

arteriosclerosis, severe hypertension, hyperthyroidism,

agitated states, or glaucoma.

Because diethylpropion is related to the

amphetamines, the potential for abuse is high; therefore,

its use is contraindicated in patients with a history of

substance abuse.

As with phentermine, use of diethylpropion should

be avoided in patients concomitantly receiving or having

received an MAOI within the preceding 14 days to prevent

hypertensive crisis.

Diethylpropion

This sympathomimetic amine exudes similar

pharmacologic activity as the amphetamines, resulting in

CNS stimulation and appetite suppression. This drug is

indicated for shortterm use in conjunction with a reduced-

calorie diet and exercise in obese patients with BMIs of 30

kg/m2 or greater after failed attempts of diet and exercise

alone.

Doses Diethylpropion is available as both an immediate-

and a controlled-release product. In conjunction with a

reduced calorie diet and/or exercise, dose diethylpropion

(immediate release) 25 mg three times a day before meals

or 75 mg (controlled release) once a day, usually

midmorning

Adverse effect:

Use of diethylpropion for a period longer than 3

months is associated with an increased risk for

development of pulmonary hypertension.

common CNS adverse effects included

overstimulation, restlessness, dizziness, insomnia,

euphoria, dysphoria, tremor, nervousness, drowsiness,

mydriasis, and blurred vision. In addition, diethylpropion

can decrease the seizure threshold, subsequently increasing

a patient’s risk for an epileptic event.

Other organ systems also can adversely be affected,

resulting in tachycardia, elevated blood pressure,

palpitations, dry mouth, GIT disturbance, impotence or

change in libido, gynecomastia, and bone marrow

suppression.

Contraindications:

Patients with pulmonary hypertension, advanced

arteriosclerosis, severe hypertension, hyperthyroidism,

agitated states, or glaucoma.

Because diethylpropion is related to the

amphetamines, the potential for abuse is high; therefore,

its use is contraindicated in patients with a history of

substance abuse.

As with phentermine, use of diethylpropion should

be avoided in patients concomitantly receiving or having

received an MAOI within the preceding 14 days to prevent

hypertensive crisis.

Diethylpropion

Adverse effect:

Use of diethylpropion for a period longer than 3 months

is associated with an increased risk for development of

pulmonary hypertension.

common CNS adverse effects included overstimulation,

restlessness, dizziness, insomnia, euphoria, dysphoria,

tremor, nervousness, drowsiness, mydriasis, and blurred

vision.

Other organ systems also can adversely be affected,

resulting in tachycardia, elevated blood pressure,

palpitations, dry mouth, GIT disturbance, impotence or

change in libido, gynecomastia, and bone marrow

suppression.

Diethylpropion

Contraindications:

Patients with pulmonary hypertension, advanced

arteriosclerosis, severe hypertension, hyperthyroidism,

agitated states, or glaucoma.

Because diethylpropion is related to the amphetamines,

the potential for abuse is high; therefore, its use is

contraindicated in patients with a history of substance

abuse.

As with phentermine, use of diethylpropion should be

avoided in patients concomitantly receiving or having

received an MAOI within the preceding 14 days to

prevent hypertensive crisis.

Surgical Intervention

Weight reduction (bariatric) surgery is an option for

patients whose BMIs are 40 kg/m2 or greater, or 35 kg/m2

or greater in the presence of other comorbid conditions

and who have failed more conventional approaches to

weight loss.Surgery is warranted when other treatment

attempts have failed in severely obese patients (BMI of 40

kg/m2 or greater, or 35 kg/m2 or greater with obesity-

related risk factors).

Surgical Intervention

There are two basic surgical techniques:

1. gastric bypass—the full partitioning of the proximal

gastric segment into a jejunal loop of the intestine—

whereby weight loss is induced through both

malabsorption of food and limited gastric

capacityfigure below

2. gastroplasty—incomplete partitioning at the proximal

gastric segment

OUTCOME EVALUATION

Successful management of overweight and obesity is

determined by the ability the treatment plan has to

(a) Prevent weight gain

(b) Reduce and maintain a lower body weight,

(c) Decrease the risk of obesity-related comorbidities.