The Endocannabinoid System as a Pharmacologic Target in Treating Obesity

1. The Endocannabinoid System as a Pharmacologic Target in Treating Obesity Lauren Kerrick Braden Advisor: Dr. Hadley Spring 2007

2. Overview • Obesity epidemic and cost • Brief overview of the endocannabinoid system • Examination of the drug rimonabant • Potential impact of this drug

3. 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)

4. 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.

5. 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.

6. 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.

7. 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.

8. 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

9. 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)

10. 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

11. 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

12. 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.

13. 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

14. 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.

15. Rimonabant Clinical Trials • RIO- Europe • RIO- North America • RIO- Lipids • RIO- Diabetes

16. 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

17. 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.

18. 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.

19. 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.

20. 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.

21. 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.

22. 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.

23. 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.

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