The Endocannabinoid System as a Pharmacologic Target in Treating Obesity

Lauren Kerrick Braden

Advisor: Dr. Hadley

Spring 2007

Overview

Obesity epidemic and cost

Brief overview of the endocannabinoid system

Examination of the drug rimonabant

Potential impact of this drug

Obesity Facts

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

Must have at least 3 of the factors present:– 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

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

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

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

Receptors are G-coupled protein receptors 2 main receptors

– CB1: found on the brain, adipose tissue, gastrointestinal tract, liver, heart, and skeletal muscles.

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

2 Receptor Ligands:– 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

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

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

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)

– Recall that hemoglobin A1C is a blood test that determines overall glucose control over about a three month period

–

Rimonabant Findings

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

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

Currently under review by the FDA here

Rimonabant Clinical Trials

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

RIO- Europe

RIO- North America

RIO- Lipids

RIO- Diabetes

Rimonabant Clinical Trials

Criteria for involvement in the trials:– 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. This is the fourth trial that is not yet published

Rimonabant Clinical Trials

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 TrialResults

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 TrialResults

RIO- Europe:

– Patients assigned to take 20mg of rimonabant were able to lose at least 5% of their initial body weight.

Almost 40% were able to lose 10% of their initial body weight.

Rimonabant Clinical TrialResults

RIO- North America– This study was two years in length, as opposed to

RIO- Europe which was one year in length 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 TrialResults

In addition to waist circumference and weight loss, other risk factors were also analyzed.– Improved levels of insulin resistance– Decreased levels of C-reactive protein– Increased levels of adiponectin

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

In addition to waist circumference and weight loss, other risk factors were also analyzed.

– Decrease in triglycerides– Increase in HDL-C

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

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.

References Bahr BA, Karanian DA, Makanji SS, Makriyannis A. Targeting the endocannabinoid system in treating brain

disorders. Expert Opin Investig Drugs. 2006 Apr;15(4):351-65. Bramlage P, Muhlen I, Randeva H, Spanswick D, Lehnert H. Cardiovascular risk management by blocking the

endocannabinoid system. Exp Clin Endocrinol Diabetes. 2006 Feb;114(2):75-81. Cannon CP. The endocannabinoid system: a new approach to control cardiovascular disease. Clin Cornerstone.

2005;7(2-3):17-26. Cooper SJ. Endocannabinoids and food consumption: comparisons with benzodiazepine and opioid palatability-

dependent appetite. Eur J Pharmacol. 2004 Oct 1;500(1-3):37-49. Cox SL. Rimonabant hydrochloride: an investigational agent for the management of cardiovascular risk factors.

Drugs Today (Barc). 2005 Aug;41(8):499-508. Despres JP, Golay A, Sjostrom L. Effects of rimonabant on metabolic risk factors in overweight patients with

dyslipidemia. N Engl J Med. 2005 Nov 17;353(20):2121-34. Di Marzo V, Matias I. Endocannabinoid control of food intake and energy balance. Nat Neurosci. 2005

May;8(5):585-9. Gelfand EV, Cannon CP. Rimonabant: a cannabinoid receptor type 1 blocker for management of multiple

cardiometabolic risk factors. J Am Coll Cardiol. 2006 May 16;47(10):1919-26. Epub 2006 Apr 24. Kirkham TC. Endocannabinoids in the regulation of appetite and body weight. Behav Pharmacol. 2005

Sep;16(5-6):297-313. Kirkham TC, Tucci SA. Endocannabinoids in appetite control and the treatment of obesity. CNS Neurol Disord

Drug Targets. 2006 Jun;5(3):272-92. Lu D, Vemuri VK, Duclos RI Jr, Makriyannis A. The Cannabinergic System as a Target for Anti-inflammatory

Therapies. Curr Top Med Chem. 2006;6(13):1401-26. Pagotto U, Vicennati V, Pasquali R. The endocannabinoid system and the treatment of obesity. Ann Med.

2005;37(4):270-5. Pi-Sunyer FX, Aronne LJ, Heshmati HM, Devin J, Rosenstock J. Effect of rimonabant, a cannabinoid-1 receptor

blocker, on weight and cardiometabolic risk factors in overweight or obese patients: RIO-North America: a randomized controlled trial. JAMA. 2006 Feb 15;295(7):761-75.

Sander GE, Giles TD. The endocannabinoid system and cardiovascular risk: pathophysiologic role and developing therapeutic interventions. Am J Geriatr Cardiol. 2006 Jul- Aug;15(4):255-9.