Efficacy and Safety of the CB1 Cannabinoid Receptor Blocker Rimonabant: Pooled Analysis of the RIO Program

Christopher P. Cannon, M.D., F.A.C.C.; C. Richard Conti, M.D., M.A.C.C.



In This Article


Dr. Conti: I'm Richard Conti in Vienna, Austria, on the occasion of the 2007 European Congress of Cardiology. With me is Christopher Cannon, who is associate professor of medicine at Harvard University and a senior investigator of the TIMI study group at Brigham and Women's Hospital. Chris, let's talk about the new pooled analysis of the RIO programs. First, give us some background.

Dr. Cannon: The objective of the Rimonabant in Obesity (RIO) program is the management of obesity, which we all know is a growing problem. Particularly challenging is the management of the consequences of obesity; namely, components of the metabolic syndrome, like low HDL, elevated triglycerides, and glucose intolerance.

The endocannabinoid system has recently been discovered and we now recognize that this system influences a lot of these risk factors. A drug has been developed, called rimonabant, that blocks the cannabinoid receptor and has a positive impact on obesity, weight, and waist circumference, plus it improves some of the other cardiometabolic risk factors.

Dr. Conti: There have been several trials done using rimonabant. Review the data you're presenting here at ESC.

Dr. Cannon: There have been five large trials, four in obesity and one specifically evaluated the affect of the drug on diabetes: RIO North America, RIO Europe, RIO Lipids, RIO Diabetes, and a fifth trial called SERENADE, which was done in newly diagnosed diabetics. In the RIO trials for obesity the trials included a low-calorie diet and then one of two doses of rimonabant or placebo.

Across the trials there was good consistency of the findings; patients on active therapy lost about 8 or 9 kilograms while those on placebo lost 2 or 3 kilograms. There was a parallel reduction in waist circumference, which would be a more direct measure of visceral fat, which we know is very active metabolically and with adverse consequences on glucose intolerance.

Active therapy also has been associated with improvements in HDL, reductions in triglycerides, and improvements in hemoglobin A1c, elevations of adiponectin, and, importantly, a reduction in C-reactive protein by about one-quarter. Finally, just looking at what percentage of patients before versus after treatment would meet the National Cholesterol Education Program (NCEP) criteria for metabolic syndrome, it was reduced by one-third to one-half in the various trials.

So, we have an agent that blocks one receptor but it's a receptor that seems to be implicated in many of the components of metabolic syndrome or cardiometabolic risk, as it's sometimes termed now.

Dr. Conti: Almost sounds too good to be true. We should point out that the lower dose of rimonabant didn't work nearly as well as the standard higher dose, which is 20 mg.

Dr. Cannon: Exactly. And you are quite right in saying that it sounds too good. We have to balance the benefits versus potential risks, which is an issue that has come front and center in the United States in the last year or two for multiple different classes of drugs. In the case of rimonabant, major effects include some nausea and diarrhea in a small percentage of patients, but more importantly there's also an increase in psychiatric events. The FDA reviewed rimonabant trial data recently and there was about a two-fold increase in the percentage of patients who reported depressive symptoms or anxiety. It's important to note that the absolute rates are in the range of 2-4% of patients being treated for obesity. Depression and anxiety are the key side effects for us to look at very carefully in managing and selecting patients for this therapy.

Dr. Conti: When we talk about depression, are we talking about psychotic depression or just feeling down in the dumps?

Dr. Cannon: Well, the adverse events included both; depressive symptoms were more likely but when measured carefully, but some patients did experience major depression.

The trials specifically excluded patients with major depression. So, in Europe, where this drug is available, it's contraindicated in patients with ongoing major depression or, at the extreme, suicidal ideation. And it is now recommended, on the basis of a new analysis, that use of this drug be avoided in patients with a prior history of major depression.

Dr. Conti: I assume that being on an antidepressant is a contraindication to using this drug. Is that correct?

Dr. Cannon: Currently, yes, and there are studies specifically looking at that question. One interesting analysis on safety stratified those who had a prior history of depressive symptoms; while these patients accounted for about 8% of the overall group, they accounted for nearly half the number of patients who developed depression. So, these patients with a history of depression had an eight-fold higher risk of developing depressive symptoms on placebo or rimonabant than those without a prior history of depression. Consequently, the European package insert now advises caution in patients who have a prior history of depressive symptoms or depression.

Dr. Conti: If you stop the drug does the depression go away?

Dr. Cannon: According to the data, it's largely reversible and European labeling notes that if a person develops depressive symptoms then you should stop the drug. Very practical guidelines coming from the European Regulatory Agency on how to identify patients who are at low risk of developing the major side effects and who could get all those benefits while avoiding this drug in patients who are higher risk of developing side effects.

Dr. Conti: What's the status of the drug in the U.S.?

Dr. Cannon: The focus of the FDA has been safety and they are taking a very careful stance. Currently, they are asking for more data.

Dr. Conti: Are there any data in obese children?

Dr. Cannon: I'm not aware of trial data in children. I do know a number of new studies are planned or underway, the largest of which is a cardiovascular outcomes trial that Deepak Bhatt is leading from the Cleveland Clinic. It will enroll 17,000 patients - about half of whom are enrolled presently – and will look at whether these improvements in risk factors associated with rimonabant therapy translates into a reduction in cardiovascular events.

Dr. Conti: The reason I asked about data in children is that the incidence of diabetes and obesity in children is skyrocketing; I have friends in endocrinology and diabetes who are seeing type 2 diabetes in 12- and 13-year-olds. I just wonder whether anybody's thinking about these children, because if something is not done these children will be in our cath labs at age 30 not at age 60.

Dr. Cannon: It's certainly a problem that's getting worse; even in adults we had data presented here showing a marked increase in both obesity and diabetes in the EUROASPIRE surveys. It's a growing problem all around.

Dr. Conti: Anything else you want to add?

Dr. Cannon: The rimonabant studies are a lesson in looking at new agents and balancing the benefits and risks. What are the benefits? What are the side effects? And then how can we target the agent to patients who benefit most? We do risk stratifications in acute coronary syndromes and that's something we can apply in other areas of cardiology, too.

Dr. Conti: And we'll leave it at that. Thanks, Chris, for coming to ACCEL.

Dr. Cannon: Thanks for the invitation.


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.
Post as: