Transcript New drugs in the treatment of obesity

The Endocannabinoid System as a
Pharmacologic Target in Treating
Obesity
Lauren Kerrick Braden
Advisor: Dr. Hadley
Spring 2007
Overview
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Obesity epidemic and cost
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Brief overview of the endocannabinoid
system
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Examination of the drug rimonabant
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Potential impact of this drug
Obesity Facts
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Obesity is the major risk factor for Type 2 Diabetes
Other health issues related to diabetes include
increased risk for cardiovascular disease, myocardial
infarction, coronary artery disease, and
cerebrovascular accidents.
Estimated cost associated with cardiovascular
disease in 2005 was $393.5 billion, and the
estimated cost associated with diabetes was $132
billion (Hogan 2003)
Metabolic Syndrome
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Must have at least 3 of the factors present:
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Increased blood pressure (130/85)
Decreased HDL-C (<40 mg/dl)
Increased triglycerides (>150 mg/dl)
Increased blood glucose levels (FBG>100 mg/dl)
Abdominal obesity
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Abdominal obesity is a better predictor of cardiovascular
disease than overall obesity because the free fatty acid levels
associated with abdominal obesity inhibit the insulin signaling
mechanism.
Treatment of Obesity Related Diseases
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Obesity can be improved through diet and
exercise.
However, it is difficult to get patients to
adhere to this advice.
There are now new pharmacologic agents
that can be used to curb appetite and
therefore lead to weight loss.
Endocannabinoid System
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This is one system that has been found in
humans that stimulates appetite.
Plays a role in regulating energy balance,
eating behaviors, lipogenesis, and glucose
homeostasis.
Found to be overactive in obese individuals.
Basics of the Endocannabinoid System
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Receptors are G-coupled protein receptors
2 main receptors
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CB1: found on the brain, adipose tissue,
gastrointestinal tract, liver, heart, and skeletal
muscles.
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These inhibit neurotransmitter release when activated
CB2: found primarily in the immune system, and
has not been found to play a role in appetite
regulation.
Basics of the Endocannabinoid System
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2 Receptor Ligands:
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2-AG and AEA
Act as agonists on the CB1 receptors
These are referred to as the endocannabinoids
Once activated, the 2-AG and AEA are released
into the presynaptic space and activate the CB1
receptors
Inhibits release of neurotransmitters into the
synaptic space
Basics of the Endocannabinoid System
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This inhibition leads to a decrease in
adenylyl cyclase and intracellular calcium
These are involved in controlling many of the
signaling processes in the brain
Determined that the endocannabinoid
system is overactive in obese individuals
(Plutzky 2006)
Endocannabinoid System as a Weight
Loss Target
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Since we have an understanding of how the
endocannabinoid system works,
pharmacologic treatments can be designed
to manipulate the system
Rimonabant is a CB1 receptor antagonist
that functions to curb appetite and therefore
helps patients to lose weight
Rimonabant Findings
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One study analyzed patients currently taking a
sulfonylurea or metformin.
Rimonabant was added
The addition of rimonabant caused an overall
decrease in the hemoglobin A1C’s of these patients
by 0.6% (Giles 2006)
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Recall that hemoglobin A1C is a blood test that determines
overall glucose control over about a three month period
Rimonabant Findings
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Another study compared the amount of rimonabant
given to the amount of weight lost.
Patients were given rimonabant in doses of 5mg,
10mg, and 20mg over a period of 4 months.
This lead to a weight loss in patients of 3.5kg, 3.9kg,
and 4.4kg, respectively (Bramlage 2006).
The more rimonabant given, the greater the amount
of overall weight loss.
Rimonabant Clinical Trials
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Rimonabant was approved in June 2006 in
Europe as an adjunct to diet and exercise
treatment for treating obese patients with risk
factors such as type 2 diabetes and
dyslipidemia
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Currently under review by the FDA here
Rimonabant Clinical Trials
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The Rimonabant in Obesity Studies (RIO)
has conducted phase three clinical trials to
determine the drug’s efficacy.
To date, there has been three published
randomized, double- blind, placebo
controlled trials with a fourth trial underway.
Rimonabant Clinical Trials
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RIO- Europe
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RIO- North America
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RIO- Lipids
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RIO- Diabetes
Rimonabant Clinical Trials
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Criteria for involvement in the trials:
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Obese (BMI of >30 or BMI >27 with treated or
untreated hypertension or dyslipidemia)
RIO- Lipids: Must have dyslipidemia
RIO- Diabetes: Must meet the diagnostic criteria
for dabetes.
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This is the fourth trial that is not yet published
Rimonabant Clinical Trials
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Each study randomly assigned patients to
take either a placebo or rimonabant (either
5mg or 20mg).
Participants also reduced their caloric intake
consuming 600 calories less than the amount
of calories needed to maintain their current
weight.
Rimonabant Clinical Trial
Results
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Patients taking the 20mg of rimonabant
experienced a clinically significant decrease
in weight and waist circumference.
Patients taking 5mg of rimonabant did not
experience as much weight loss and waist
circumference decrease as those on 20mg.
Rimonabant Clinical Trial
Results
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RIO- Europe:
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Patients assigned to take 20mg of rimonabant
were able to lose at least 5% of their initial body
weight.
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Almost 40% were able to lose 10% of their initial body
weight.
Rimonabant Clinical Trial
Results
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RIO- North America
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This study was two years in length, as opposed to
RIO- Europe which was one year in length
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After one year, patients taking 20mg rimonabant were
either switched to placebo or continued with the 20mg of
rimonabant.
Patients switched to the placebo after one year
failed to maintain their weight loss, whereas
weight loss continued in those patients on the
20mg rimonabant.
Rimonabant Clinical Trial
Results
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In addition to waist circumference and weight
loss, other risk factors were also analyzed.
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Improved levels of insulin resistance
Decreased levels of C-reactive protein
Increased levels of adiponectin
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Adiponectin is a hormone associated with obesity.
Levels are normally suppressed in obese individuals
Rimonabant improved adiponectin by 58%, whereas the
group receiving placebo showed no change in
adiponectin levels.
Rimonabant Clinical Trial
Results
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In addition to waist circumference and weight loss,
other risk factors were also analyzed.
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Decrease in triglycerides
Increase in HDL-C
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Some of the increase in HDL-C could be accounted for by
weight loss alone.
This was adjusted by the RIO investigators
Demonstrated that rimonabant was able to increase HDL-C by
7.2% in those patients taking the rimonabant for one year.
Only 4.2% of this HDL-C increase was attributed to weight loss
alone.
Conclusion
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By understanding the basic principles of the
endocannabinoid pathway, pharmacologic
treatments can b designed to target the system.
Blocking the endocannabinoid system will help to
suppress appetite and promote weight loss.
Weight loss will help to manage diseases such as
diabetes.
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