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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.