OBAT ANTI OBESITAS

Nurul Hiedayati

Definisi WHO
Overweight and obesity are defined as
abnormal or excessive fat accumulation that
presents a risk to health
BMI 25 kg/m2 : overweight
BMI 30 kg/m2 : obesity

Facts about overweight and obesity

WHOs latest projections indicate that globally in 2005:
approximately 1.6 billion adults (age 15+) were
overweight;
at least 400 million adults were obese.
WHO further projects that by 2015,
approximately 2.3 billion adults will be overweight and
more than 700 million will be obese.
At least 20 million children under the age of 5 years are
overweight.

Melnikova et al. Nature Reviews Drug Discovery 5, 369370 (May 2006) | doi:10.1038/nrd2037

Obesity risk factor for many diseases :

sudden death is more common in those
who are naturally fat than in the lean
(hippocrates)
FDA - cited in Bray, G.A. Endocrinol Metab Clin N.
Amer 32 (2003) 787-804

What causes obesity and overweight?

a global shift in diet towards increased intake
of energy-dense foods that are high in fat and
sugars but low in vitamins, minerals and other
micronutrients; and
a trend towards decreased physical activity
due to the increasingly sedentary nature of
many forms of work, changing modes of
transportation, and increasing urbanization.

 Genetic factors also contribute to this

imbalance; for example, the Thrifty-gene
hypothesis proposes that humans particularly
prone to famine have evolved to favour the
storage of excess calories in the form of fat

Raised body mass index is a major risk

factor for chronic diseases such as
Cardiovascular disease (mainly heart disease
and stroke)
Diabetes which has rapidly become a global
epidemic.
Musculoskeletal disorders especially
osteoarthritis.
Some cancers (endometrial, breast, and
colon).

Obesity comorbidities
Cardiovascular: hypertension,
coronary artery disease, angina
pectoris, congestive heart failure
Cerebrovascular: stroke
Hyperlipidemia
Metabolic syndrome/type 2 DM
Cholelithiasis
Gout, uric acid nephrolithiasis

Osteoarthritis
Obstructive sleep apnea,
hypoventilation
Hyperandrogenism, hirsutism,
irregular menses, complications
of pregnancy, stress incontinence
Malignancies: breast,
endometrium, colon, prostate
Increased surgical risk
Psychological disorders

10

The National Institute for Health and Clinical Excellence

(NICE) published guidance on managing obesity in
childhood and adolescence in 2006

identifying lifestyle modification as the initial

management strategy
identifying antiobesity drug therapy
and bariatric surgery

Approval
BMI 30 kg/m2
BMI > 27 kg/m2 when 2 or more related
complication like: T2DM, Hypertension, heart
disease, etc

INDICATIONS FOR USE OF OBESITY DRUGS

A combined intervention of behavior therapy, dietary

changes and increased physical activity should be
maintained for at least 6 months before considering
pharmacotherapy.

NHLBI Obesity Education Initiative, Expert Panel on the Identification, Evaluation, and Treatment of
Overweight and Obesity in Adults

Basic Rules
Never for cosmetic purposes
Always combine with healthy eating and
physical exercise
Subject should have tried weight loss thru diet
and physical exercise

Pharmacology of Obesity

Potential Strategies for Anti-Obesity Drug Action

Reducing food intake. Either amplify effects of signals/factors that
inhibit food intake or block signals/factors that augment food intake
Blocking nutrient absorption (especially fat or carbohydrates) in
the intestine.
Increasing thermogenesis. Either increase metabolism and
dissipate food energy as heat or increase energy expenditure
through the enhancement of physical activity.
Modulating fat metabolism/storage. Regulate fat
synthesis/breakdown by making appropriate adjustments to food
intake or energy expenditure.
Modulating the central regulation of body weight. Either alter the
internal set point or modulate the signals presented regarding fat
stores.

Currently Available Agents Indicated for Treatment

of Obesity
Generic/Brand Name
Orlistat/Xenical

Sibutramine/Meridia

Phentermine/ Adipex,
Fastin, Ionamin and
others

Usual Dose

Mechanism of Action

Side Effects

120 mg with each

meal

Peripheral: Blocks
absorption of about
30% of consumed fat

GI symptoms (oily

5-15 mg/d

Central: Inhibits
synaptic reuptake of
norepinephrine and
serotonin

Dry mouth,
constipation, headache,
insomnia, increased
blood pressure,
tachycardia

15-37.5 mg per
day as a single or
split dose

Central: Stimulates
release of
norepinephrine

CNS stimulation,
tachycardia, dry mouth,
insomnia, palpitations

spotting, flatus with

discharge, fecal urgency,
oily stools, incontinence)

Agents sometimes used for Treatment of Obesity

NOT Indicated or FDA approved
Generic/Brand Name

Usual Dose

Mechanism of Action

Side Effects

ephedrine+/-caffeine
"Elsinore"pill

Varies: usually
75-150 mg
ephedrine and
100-150 mg
caffeine

Central: Stimulates
adrenergic receptors

CNS stimulation,
tachycardia, dry
mouth, insomnia,
palpitations

Bupropion/Wellbutrin

100-300 mg/d

Central: Inhibits
reuptake of dopamine
norepinephrine and
serotonin

CNS stimulation, dry

mouth, headache, GI
effects

CNS: paresthesia,
Uncertain: Central ?
Topiramate/Topamax

96-192 mg/d

fatigue, dizziness,
memory difficulty,
concentration difficulty,
and depression

INDICATIONS FOR USE OF OBESITY DRUGS

BMI of 30 kg/m or more or a BMI of 27 kg/m or
more with comorbid condition
Understand that drug therapy is adjunctive to
lifestyle intervention
Have realistic expectations about weight loss
goals and outcomes
Demonstrate readiness for change
Are unable to lose/maintain weight with lifestyle
change alone
Comply with medication use
Have no medical or psychiatric contraindications

ADDITIONAL CONSIDERATIONS
WHEN USING ANTI-OBESITY DRUGS
Weight loss drugs should never be used without continued
concomitant lifestyle modifications and as part of a
comprehensive weight loss program.
Continual assessment of drug therapy for efficacy and safety is
necessary.
If the drug is efficacious in helping the patient to lose and/or
maintain weight loss and there are no serious adverse effects, it
can be continued.
If not, it should be discontinued.
NHLBI Obesity Education Initiative, Expert Panel on the Identification, Evaluation, and Treatment of
Overweight and Obesity in Adults

CONTRAINDICATIONS OR CAUTIONS TO THE

USE OF OBESITY DRUGS
Pregnancy or lactation
Unstable cardiac disease
Uncontrolled hypertension (SBP >180, DBP > 110 mmHg)
Unstable severe systemic illness
Unstable psychiatric disorder or history of anorexia
Other drug therapy, if incompatible (eg MAO inhibitors,
migraine drugs, adrenergic agents, arrhythmic potential)
Closed angle glaucoma (caution)
General anesthesia

NHLBI Obesity Education Initiative, Expert Panel on the Identification, Evaluation, and Treatment of
Overweight and Obesity in Adults

Pharmacology of Drugs Currently

Approved for Treatment of Obesity

FDA and UK approved antiobesity

the gastric and pancreatic lipase inhibitor
orlistat (licensed for adults in 1998),
and the serotonin and noradrenergic reuptake
inhibitor sibutramine (licensed for adults in
2001).

National Institute for Health and Clinical Excellence

criteria for use of orlistat and sibutramine in children
and adolescents

Sibutramine (Meridia)
Appetite suppressant that works by blocking reuptake of
serotonin and norepinephrine.
Some experts have postulated that this agent may be the
most effective in helping maintain weight loss.
Maintaining weight loss has long been the major downfall to
most diet programs.
Until recently, the longest clinical trials with this agent have
lasted 1 year.

Sibutramine (Meridia) Indications

Among obese patients who should undergo drug therapy, sibutramine
works best for those who:

Experience difficulty controlling food intake

Do not feel full
Think about food a lot
Do not have increased cardiovascular disease risk or multiple risk
factors
Are younger
Sibutramine is taken once daily with or without food.

Sibutramine (Meridia)
Contraindications
The use of sibutramine is contraindicated in
patients:
Taking concomitant monoamine oxidase
inhibitor (MAOI) therapy
With anorexia nervosa
Using any other centrally-acting appetite
suppressant
With hypersensitivity to ingredients of
sibutramine

Sibutramine (Meridia)
Contraindications
In addition, sibutramine should not be used by
patients who have:
uncontrolled hypertension
coronary heart disease
congestive heart failure
Arrhythmias
stroke
severe renal or liver dysfunction

Sibutramine should be used with caution in

patients with narrow-angle glaucoma.

Sibutramine
Sibutramine Trial of Obesity Reduction and
Maintenance (STORM)
Half of the patients who began therapy achieved a 10%
weight loss
More than a third of these patients maintained that weight
loss for 2 years.
As expected, the subjects who were able to maintain weight
loss experienced predictable improvement in metabolic risk
factors.

Sibutramine Side Effects

Can result in dry mouth, constipation,

headache, insomnia, increased blood
pressure, tachycardia.
Should monitor all patients once a month for
hypertension and side effects
Should take in the morning to avoid insomnia

Orlistat (Xenical)
Pancreatic lipase inhibitor that blocks the absorption of up to
one third of ingested fat.
In addition to helping reduce weight, orlistat has been shown
to also:
lower plasma low-density lipoprotein cholesterol (LDL) cholesterol
levels.
The decline in LDL cholesterol is greater than that expected due to
weight loss alone.
Lower HgbA1C in diabetic patients

Orlistat (Xenical) Indications

Among obese patients who meet the criteria for
anti-obesity drug therapy, orlistat is most likely to
benefit those who:

Do not feel hungry

Are not preoccupied with food
Eat out or order-in often
Have increased cardiovascular disease risk or multiple
cardiovascular risk factors
Are older
Take multiple medications

Orlistat is taken 3 times daily with meals

Orlistat
Effect of orlistat on dietary cholesterol absorption
18 obese (average BMI, 37 kg/m2) subjects with and
without orlistat therapy.
Radiolabeled cholesterol tracer was given as part of a meal

Orlistat treatment was associated with a reduction in

cholesterol absorption from 53% to 40%, representing a
25% reduction in cholesterol absorption (P < .05).
B. Mittendorfer, et al.

Orlistat

Figure 3. A: Data from volunteers randomized to Int + P. B: Data from volunteers randomized
to Int + O. Baseline for plasma FFA ( ) and during a 4-h insulin infusion and are plotted with
corresponding values at 6 months ( ). There were significant postintervention changes in
plasma FFA in both groups. The changes were greater with Int + O. *P < 0.05; P < 0.01.
[Diabetes Care 27(1):33-40, 2004. 2004 American Diabetes Association, Inc.]

Orlistat

EGP = endogenous glucose production and Rd = glucose utilization

[Diabetes Care 27(1):33-40, 2004. 2004 American Diabetes Association, Inc.]

Orlistat
6 obese (BMI, 38 kg/m2), insulin-resistant males treated with
orlistat for 3 months.
All subjects were instructed to maintain their weight at a
constant level.
Using a euglycemic-hyperinsulinemic clamp technique, these
investigators measured insulin sensitivity before starting
orlistat, after 3 months of therapy, and at 3 months after
stopping therapy.
Insulin sensitivity increased by 42% after 3 months of orlistat
treatment despite no change in weight.
Insulin sensitivity declined to baseline again after stopping
orlistat treatment.
D. B. Dahl et al.

Orlistat- Effect on HgbA1C in T2DM

The improvement
in HbA1c achieved with
orlistat therapy
exceeded that of the placebo
group and there was a 0.62%
improvement
in HbA1c relative to the
baseline value for the
participants randomized to
orlistat.

Figure 4HbA1c over 1 year of double-blind treatment with placebo (E) or 120 mg orlistat (F).
P0.002, least-squares mean difference from placebo in the change from baseline over 52 weeks.

DIABETES CARE, VOLUME 25, NUMBER 6, JUNE 2002

Orlistat- XENDOS
4-year, double-blind, prospective study
3,305 patients we randomized to lifestyle
changes plus either orlistat 120 mg or placebo,
three times daily.
Participants had a BMI 30 kg/m2 and normal
(79%) or impaired (21%) glucose tolerance
(IGT).
Primary endpoints were time to onset of type
2 diabetes and change in body weight.

Orlistat- XENDOS

Orlistat- XENDOS
After 4 years treatment, the cumulative
incidence of diabetes was:
9.0% with placebo
6.2% with orlistat

This corresponds to a risk reduction of 37.3% in

all patients (P 0.0032).
Risk reduction in patients with IGT was 45.0%

Orlistat- XENDOS

Orlistat Side effects

Because it blocks intestinal absorption of fat it can result in
diarrhea and steatorrhea
This is minimized by maintaining a strict low fat diet (<30% of
diet)
Another concern is the loss of fat soluble vitamins with a
potential for malnutrition.
To prevent this, recommend a daily multivitamin for all
patients on this therapy

Investigational Agents for

Treatment of Obesity

Conclusion

Pharmacotherapy of Obesity
Diet/lifestyle changes remain the mainstay of the treatment
of obesity
In patients not reaching goals, drugs can be an important
tool
Expect only modest weight loss at best with current drugs
Be aware of Rx indications and contraindications
Off label use of non-indicated products is not recommended
Investigational agents may offer hope for treatment of
obesity in the future