Drugs for Obesity

April Dawn Rallos-Lucero, MD, DipIBLM

Overview
Obesity
• A state of excess adipose tissue
mass

• Although often viewed as equivalent

to increased body weight, this need
not be the case—lean but very
muscular individuals may be
overweight by numerical standards
without having increased adiposity.
Obesity
• Although not a direct measure of adiposity, the most widely used method
to gauge obesity is the body mass index (BMI), which is equal to:
Asia Pacific Guidelines
Pathologic Consequences
• Increase in mortality, with a 50–
100% increased risk of death
from all causes compared to normal-
weight individuals, mostly due to
cardiovascular causes

• Obesity and overweight together are

the second leading cause of
preventable death in the United
States
Pathologic Consequences
• Insulin Resistance and Type 2 Diabetes
➢ A major risk factor for diabetes
➢ As many as 80% of patients with type 2 diabetes mellitus are obese

• Reproductive Disorders
➢ Male: hypogonadism, gynecomastia

➢ Female: Most obese women with oligomenorrhea have polycystic ovarian syndrome

(PCOS), with its associated anovulation and ovarian hyperandrogenism; 40% of

women with PCOS are obese.
Pathologic Consequences
• Cardiovascular Disease
➢ Independent risk factor for cardiovascular disease in men and women (including
coronary disease, stroke, and congestive heart failure)
➢ Atherogenic lipid profile (increased LDL, VLDL, & triglycerides; decreased HDL)
➢ Associated with hypertension

• Hepatobiliary Disease
➢ Frequently associated with nonalcoholic fatty liver disease (NAFLD)
➢ Progresses in a subset to inflammatory nonalcoholic steatohepatitis (NASH) and
more rarely to cirrhosis and hepatocellular carcinoma
➢ Higher incidence of gallstones, particularly cholesterol gallstones
Pathologic Consequences
• Cancer
➢ Males: associated with higher mortality from cancer of the esophagus, colon,
rectum, pancreas, liver, and prostate
➢ Females: associated with higher mortality from cancer of the gallbladder, bile ducts,
breasts, endometrium, cervix, and ovaries

• Bone, Joint, & Cutaneous Disease

➢ Increased risk of osteoarthritis
➢ Acanthosis nigricans: darkening and thickening of the skinfolds on the neck, elbows,
and dorsal interphalangeal spaces
Obesity
An individual whose BMI is greater than 30
or greater than 27 with at least two
comorbidities (for example, hypertension
and diabetes) is considered a potential
candidate for pharmacological treatment of
obesity.
Overview
• Majority of drugs for obesity: short-term indication

• Older medication approved for short-term usage are

the anorexiants phentermine and diethylpropion

• Lipase inhibitor: orlistat

• Drugs for obesity are considered effective if they

demonstrate at least a 5% greater reduction in body
weight as compared to placebo (no treatment).

• The medications discussed in this chapter have been

shown in clinical trials to help patients lose
approximately 5% to 10% of their body weight.
Drugs for Obesity
 Phentermine

Diethylpropion
Anorexiants
Appetite Suppressants
Mode of Action: Phentermine
• Increases the release of norepinephrine and dopamine from the nerve
terminals and inhibits reuptake of these neurotransmitters, thereby
increasing levels of neurotransmitters in the brain.

• The increase in norepinephrine signals a “fight-or-flight” response by the

body, which, in turn, decreases appetite.

Mode of Action: Diethylpropion
• Has similar effects on norepinephrine

• Tolerance to the weight loss effect

develops within weeks, and weight loss
typically plateaus.

• An increase in the dosage generally does

not result in further weight loss, and
discontinuation of the drug is usually
recommended once the plateau is
reached.
Adverse Effects
• All of the anorexiants are classified as CONTROLLED SUBSTANCES due to
the potential for dependence or abuse.

• COMMON: dry mouth, headache, insomnia, and constipation

• Increased heart rate and blood pressure

➢ Avoid in patients with a history of uncontrolled hypertension, cardiovascular disease,

arrhythmias, heart failure, or stroke.

➢ Concomitant use of anorexiants with monoamine oxidase inhibitors (MAOIs) or other

sympathomimetics should be avoided.
Lipase Inhibitors
Lipase Inhibitors: Orlistat
• Currently the only available agent

• It is indicated for weight loss or

weight maintenance

• The clinical utility of orlistat is

limited by gastrointestinal
adverse effects.
Mode of Action: Orlistat
• Inhibits gastric and pancreatic lipases, thus decreasing
the breakdown of dietary fat into smaller molecules that
can be absorbed.

• Decreases fat absorption by about 30%

• The loss of calories from decreased absorption of fat

is the main cause of weight loss.

• However, adverse gastrointestinal effects associated with

the drug may also contribute to an overall decreased
intake of food.
Adverse Effects
• Most common: gastrointestinal symptoms, such as oily spotting,
flatulence with discharge, fecal urgency, and increased defecation

• These effects may be minimized through a low-fat diet and the use of
concomitant cholestyramine.

• Contraindicated in pregnancy and in patients with chronic

malabsorption syndrome or cholestasis.
Adverse Effects
• Also interferes with the absorption of fat-soluble vitamins and β-
carotene

• Advise to take a multivitamin supplement that contains vitamins A, D, E,

and K and also β-carotene

• The vitamin supplement should not be taken within 2 hours of orlistat

Serotonin Agonists
Lorcaserin
• A newer serotonin agonist, with selectivity for the 2C serotonin receptor (5-
HT2C)

• Used for chronic weight management

• Previous serotonin agonists used for weight loss were pulled from the market
following an increase in potentially fatal adverse effects, including valvular
heart disease.

• It is believed that valvulopathy, which may lead to pulmonary hypertension, is

linked to 5-HT2B receptors.
Mode of Action: Lorcaserin
Selectively activates 5-HT2C receptors
are almost exclusively found in the central nervous system

Stimulates pro-opiomelanocortin neurons

which activate melanocortin receptors

Decrease in appetite
If a patient does not lose at least 5% of their body weight after 12 weeks of use, the drug should be
discontinued.
Most Common Adverse Effects: Lorcaserin

Nausea Dizziness
Constipation Headache
Dry mouth Lethargy
Adverse Effects: Lorcaserin
• Although rare, mood changes and suicidal ideation can occur.

• The development of life-threatening serotonin syndrome or neuroleptic

malignant syndrome has been reported with the use of serotonin
agonists. Therefore, patients should be monitored for the emergence of
these conditions while on lorcaserin.
Adverse Effects
• Avoid concomitant use with selective serotonin reuptake inhibitors, serotonin–
norepinephrine reuptake inhibitors, MAOIs, or other serotonergic drugs should be
avoided

➢ Increased risk of serotonin syndrome

• Although the incidence of valvulopathy was not significantly increased in studies of

lorcaserin, a 5-HT2C receptor agonist, patients should still be monitored for the
development of this condition.

• For that reason, individuals with a history of heart failure should use this agent with
caution.
Combination Drugs
Combination Drugs
• The combination of phentermine and topiramate has been approved for long-
term use in the treatment of obesity.

• In initial studies of the anticonvulsant topiramate, it was observed that patients

lost weight while taking the medication.

• This prompted further investigation into the use of topiramate for weight loss in
obese individuals.

• Because of the sedating effects of topiramate, the stimulant phentermine was

added to counteract the sedation and promote additional weight loss.
Combination Drugs
• The phentermine/topiramate combination is dosed in steps, escalating
the dose every 2 weeks, depending on the response.

• If a patient does not achieve a 5% weight loss after 12 weeks on the

highest dose of this medication, then it should be discontinued.

• Should not be stopped abruptly as SEIZURES may be precipitated

Adverse Effects

Topiramate Phentermine Note

• Cleft palate • Increased HR

• Paresthesias • Serotonin • Avoid in
• Suicidal ideation syndrome w/
MAOI
pregnancy
• Cognitive
dysfunction
Bariatric Surgery
• A treatment option for patients with
a BMI of 40 kg/m2 or greater who
instituted but failed an adequate exercise
and diet program (with or without
adjunctive drug therapy) and who present
with obesity-related comorbid conditions,
such as hypertension, impaired glucose
tolerance, diabetes mellitus,
hyperlipidemia, and obstructive sleep
apnea
Question 1
A 45-year-old female presents seeking
treatment for weight loss. She has tried
several fad diets in the past with very little
success. She exercises twice weekly at the
gym for 30 minutes and tries to watch what A. Phentermine.
she eats. Her BMI is 31 and she has diabetes B. Phentermine/topiramate.
and uncontrolled hypertension. Which of C. Orlistat.
the following medications would be most D. Diethylpropion.
appropriate to treat her obesity?
 Answer = C
• Orlistat is the only medication of
those listed that does not increase
heart rate and blood pressure.

• Since this patient’s blood pressure is

currently uncontrolled, choosing a

drug that does not affect blood
pressure would be best at this time.
Question 2

A 27-year-old recently married

female is asking about treatment
options for her obesity. She recently
stopped taking her birth control A. Phentermine.
medications, as she felt these were B. Phentermine/topiramate.
contributing to her weight gain. C. Orlistat.

Which of the following medications D. Diethylpropion.

E. Lorcaserin.
should be avoided in this patient?
Answer = B
• The topiramate component of
this medication is contraindicated in
pregnancy.

• Since this patient stopped her birth

control, she is at risk of becoming
pregnant and her fetus is at risk of
developing birth defects if she is
taking this medication.