CME Slides Forum - S. Rössner

NEW THERAPEUTIC APPROACHES TO OBESITY (CANNABINOID RECEPTOR BLOCKERS)

Stephan Rössner, Stockholm, Sweden

Chair: Vincenzo Cambi, Parma, Italy

Eberhard Ritz, Heidelberg, Germany

ROSSNER

Prof Stephan Rössner
Obesity Unit
Karolinska University Hospital
Stockholm, Sweden

Mr Chairman, Dear Colleagues thanks for the invitation. The famous Danish actor Victor Borg appeared on stage very late in life and he used to start by saying “I’m very happy to be here, as a matter of fact I’m very happy to be anywhere!” I’m happy to be here but my background is definitely not nephrology, I run the Obesity Unit at the Karolinska in Stockholm. I’m the past President of the International Association for the study of obesity and what little nephrology I’ve learnt, I’ve learnt across the dinner table from my wife. So what I’ll try to give you now is a background description, which tries to combine what we heard before.

The genetic problem is obviously there but we know that the genes haven’t changed much over the last 100.000 years whereas the environment has changed dramatically and to put a new drug rimonabant into that prospective. The situation is that we have very few drugs available for pharmaco therapy of obesity and this is actually only the third drug that is now available to most people like myself treating obesity in clinical realities.

Now, to pay attention to the part of the world where we are staying right now, geography is an interesting way to learn about the distribution of obesity over the globe and you see that this part of the world cannot flatter itself with anything but being on the top third of the obesity European league. It’s interesting to know that Greece is on the top, so much for the Mediterranean diet! And we have some countries where you have probably the best food in the world like France close to the bottom.

So we know that there is a lot of variation in how obesity develops and of course, this is a match of social, economical, geographical, political factors. You see that many of the East European countries here, for instance, top the list. Because we are today living in an – that we’ve never experienced before.

This is a painting of a painter from Iceland—and it’s called foodscape not landscape but foodscape and this is the situation, food is abundant around us 24 hours a day, 365 days per year. This was not what our genes were built to cope with.

Actually Kelly Brownell working in Philadelphia has coined the term the toxic environment. The new toxins are not heavy metals or pollutants; it’s the environment that is constantly pressing us to over consume food that is very dense in energy. This Stone Age diet was extremely low in fat and sugar, our ancestors were eating huge volumes to survive and now the combination of sugar, fat compacts food in to so small volumes that we overeat before our satiety signals have reacted properly.

Now as we heard from Professor Ritz in the beginning, it’s easy for us working with obesity to make the diagnosis in the street without even undressing the patient. I would like to point out that there are many more underlying conditions; we’ve been talking about some of them before during the symposium, than just the classical ones, the metabolic syndrome. Here is a list two circles partly overlapping where you see the metabolic pathology to the left and the mechanical to the right with some overlap. I just highlighted some of them not because they are more important but because rather little attention has been paid to them compared to the other ones. Liver steatosis for instance. We used to think that fatty liver like the fois gras was just an excess of fat in the liver, now we know that NASH, non-alcoholic steatotic hepatitis probably is quite a dangerous condition. We realised that the psychosocial complications of obesity with the stigmatisations are huge in our society. Sleep apnoea is an often-missed condition, which is under diagnosed. We know that a lot of the traffic accidents are depending on central obesity resulting in sleep apnoea with sleep arrest during the night, awakening and then daytime sleepiness causing the fact that drivers fall asleep at the wheel or have near misses as it is called. Stress incontinence is not very exciting as a scientific area of research but if we look at the financial implications of what this causes to society, this is enormous. So obesity really encompasses much more than the metabolic syndrome and this has psychosocial and also health and economical consequences. We have seen this slide before in other versions before we are far beyond the point when we discuss obesity as a cosmetic problem. This is now probably going to go past smoking as the preventable condition that will cause most deaths by the year 2007 in the United States. So we have really now an enormously dangerous epidemic upcoming here.

You see here that in this study from 2003 as it has been mentioned before with increasing BMI values the relative risk of death seems to go down. So if you are at that situation where renal insufficiency is a reality, maybe I’m too late with my attempts to prevent development. But earlier on clearly it would be beneficial, if we could do something to prevent people from arriving at this situation, which we know is related to other complications.

This is a recent slide from 2006 looking at the incident in HD patients and you see here that those who are more obese have a better outcome. As before it has been discussed what the reason is. Is there a survival advantage of the obese? Are they less likely to be transplanted? Are there age differences, race differences, genetic aspects? We just don’t know.

Earlier we have discussed the definitions and the confusion that we have witnessed in the literature over the last few years and clearly we will hear more about that in the near future. This is the recent definition which has not actually been rectified but which was discussed in the paper by Kahn recently alluded to by Professor Ritz. Here the interesting aspect is that the waist circumference although here measured by BMI but the fact that waist circumference probably is going to be a central way for us to address and define obesity as such. There are several advantages with using waist circumference not waist-hip ratio because the information content in that ratio is probably less. We know that we can have catabolism resulting in reduced muscle mass over the hips. Every patient will know how tight his or her clothes will fit. When you have to change clothes size how tight your belt is and it’s easy to talk about a change in centimetres as the result of a successful weight loss program rather than to indicate to somebody even a doctor that the BMI has fallen from 29 to 27.1 that doesn’t mean a lot to most people. So my guess is that within 10 years we will probably not use BMI any more, we might use it at the population basis and we know also that populations in many parts of the world are different and that in South East Asia people are much more vulnerable even at lower BMI levels. It has been suggested in these countries that we have 23 for overweight and 25 for obesity. Whereas as you know in Europe we have 25 and 30. So many things will happen here in the future but my prediction is that we will use waist circumference in the future. Now they are at least sex specific, they are not yet age specific but sex specific and I think when we have better long-term data on the relationship between waist circumference and morbidity and mortality we might switch over to that at a later stage.

So here are the definitions and why I bring this up again is to introduce the rimonabant question which I’ve been asked to address because that built to a great deal on the recognition of the metabolic syndrome as the treatment target.
We have discussed this before we don’t know where the metabolic syndrome is heading and we may ask the question whether it was wise from Sanofi which is the company producing rimonabant to try to attempt to introduce the drug as a treatment not for obesity but for the metabolic syndrome which clearly would have much wider applications to the cardiologic society, to the general practitioner, whereas obesity only would be a much more narrow indication and also be much more difficult to receive reimbursement for in most countries.

So this brings me to my second part of my presentation, which is an attempt to describe the endocannabinoid system, which is a fascinating newly discovered system, which seems to regulate and stabilise several aspects of lipid metabolism. Many of these endocannabinoids have been derived from polyunsaturated fatty acids such as arachidonic acid. They are not stored in granular but they are produced on demand and they can work backwards as retrograde messengers. There are a couple of different cannabinoid receptor inhibitors or agonists as well. Number 2 I’m not going to address here but that is more related to blood cell function and immunology.

So what we’re talking about here are these CB1 receptors and the CB1 receptor antagonist. Now this seems to be the way in which rimonabant is working. We have a system where feeding is related to weight increase. If you have an excess intake above expenditure, we have the association that is well known to all of you with type II diabetes and dyslipidemia but we also have from the adipose tissue the relationship with adiponectin, which is the good guy in this situation but which is reduced in obesity. We have the relationship with peripheral insulin resistance, hepatic insulin resistance and hepatic glucose output. We know that the visceral fat which actually is a very small volume, we are looking at somebody with a big belly, with the apple-shaped obesity and this maybe a guy you’ve seen slides from before but the amount of fat sitting in the true visceral region is actually very small. So if you lose 10 kg, for instance that means that you will perhaps lose only a few ectos a few hundred grams of the visceral fat. But since this is so extremely overactive it has implications for the sending out of free fatty acids into the liver and the blocking of insulin receptors resulting in hyperinsulinemia and then the whole cascade starts. We also have the relationship to the dyslipidemic problems here with these small LDL particles and the low HDL cholesterol. So the interesting thing with this CB1 A receptor blockers is that they work at three different levels. They work in the periphery both in the adipose tissue and in the liver and they also seem to work like other appetite suppressants in the brain.

What do we know clinically about rimonabant? Well we know that the FDA and the European commission in London has given preliminary acceptance so it’s likely that we will see the drug available to most prescribing doctors towards the end of this year.
What is the information based on? Well so far there are more than 6000-7000 patient studies so far. If we include the smoking cessation studies we have at least 14.000 patients studied for up to a few years. The interesting thing with rimonabant is that it seems to block a number of lust related sensations. It has been tried for obesity obviously, for excessive eating, binge eating disorders. It has been tried for smoking cessation. For alcoholism etc and somebody coined the expression and said this is the ideal drug for a monk if there is no pleasure in eating, drinking, smoking, sex well what’s life then worth?

The RIO studies focused in response to the regulatory bodies to what is needed for registration here. They concentrated on obesity only but then also on the comorbidities. The trial setup was pretty similar to allow pooling of all the data. So these were studies for up to 2 years and today we are not using very strict diets. Of course that has problems in the long term for compliance etc. So this is a typical design where you would calculate the requirements for a person imbalance and then subtract 600. At that time it was unknown where the proper dose was so most RIO trials were done with 5 and 20 mg doses.

But the 5 mg is not discussed anymore. So we’re only talking about the 20 mg dose. Rimonabant has a very long half-life of 6-9 days, 15 days in obese individuals. It is broken down in the liver and it is excreted via the faeces, which is probably a good point for a nephrologist.

Now let’s look at the results. The weight loss here is 8-9 kg which is slightly better than what we have today with the present drugs exenical and reductil ---- in the United States--- . So this is quite acceptable and results seem to be well maintained.

Apart from the weight loss what happens with the other proxy data for cardiovascular disease? The HDL increase is dramatic much more than can be expected. Triglyceride drop is also quite pronounced. So this is something that goes over and above the effect of weight loss.

The size of the – allows pooling of the data. So you see here that the HDL cholesterol increase is almost twice as much from another factor that we don’t know for certain but results in a beneficial change of the HDL cholesterol. The same thing here with triglycerides. You receive almost the same effect from non-weight loss related factors that we cannot explain at present.

In the diabetes studies with patients with only one drug oral treatment for diabetes you see that more than twice as many patients reduced their HbA1c levels below a precept level of 6.1% after 1 year of treatment.

If we come to the metabolic syndrome and pool all the data, you see similar results. They are not as impressive for diabetes but as you know from most trials, weight loss trials or other trials diabetics always fair less well than non-diabetic patients for a number of reasons which I won’t go into here but the pattern as you see here is in principal exactly the same for all groups. What do we know about the adverse events? Well this is a drug that acts in many different parts of the body but the total number of side effects is actually quite low here and if you add them all together, you come to 40% but that is the standard way of using any kind of side effects that people can think of when they’re in a treatment program.

The concern was actually depression to the degree of suicidal thoughts and that has not been documented otherwise this seems to be a pretty safe profile. First when I saw this slide I wondered about how you can achieve half a pregnancy but then I realised this was in percent and not in absolute numbers.

So my conclusions and I’m just concluding about the last part about the rimonabant part is that we now have a lot of data showing that the dose 20 mg will consistently produce reduction in weight and waist circumference, improve the metabolic characteristics. Some of them have not been addressed here by my slides and will also improve the odds for diabetic patients to reach precept target goals and these effects are maintained. Everybody realises that obesity is a chronic condition so something that just works for a few months is not interesting. We’re treating obese patients like we’re treating diabetic patients. It’s a chronic disease that requires life long attention.

I haven’t talked a lot about adiponectin but it goes up with rimonabant treatment, which might be an important marker for the future when we see adiponectin as a protector and also it does reduce the indicators for inflammation. One of the participants here in discussion discussed the aspect of obesity as a low-grade chronic inflammatory condition and in that case then rimonabant would reduce that inflammation. So rimonabant seems to be the first selected CB1 blocker that is available to us now we have to start to learn from clinical practice how it’s going to work in reality.

So let me conclude by again quoting Victor Borge who was known for his very high appearance fees who said ‘I would like to thank my parents who made this show possible and my expensive children who made it necessary’. I would like to thank the organisers who made this possible but I have to admit that it’s the obesity epidemic that’s made it necessary. Thanks for your attention.

Question: I appreciated the fact that you mentioned that the amount of visceral lipids is almost negligible. Since 60% of our body weight is fluid, do you have any indication that this approach of drug therapy will have an effect on fluid and sodium homeostasis?

Prof Rössner: I just don’t know, you know when these drugs come up for obesity, they always follow a trial pattern because every drug company knows exactly what is needed for registration and that is long-term maintained weight loss first in the general population, then in patients with the comorbidities, then in ethnic other groups, then in women and then in children. Those would be the priorities for a drug company setting up the strategy. So that’s where it all started, so I think that all these matters will come and if rimonabant has a role in the treatment of all the patients that many of you are concerned with I just can’t tell at present.

Question: Any comment on the pharmacokinetics of rimonabant in the patients with declining renal function?

Prof Rössner: Rimonabant is rapidly absorbed, it’s bound to more than 99% to albumin. It is degraded in the liver and excreted to 86% through the faeces. That is what I know but from a nephrological point of view that sounds like quite a good drug as far as I can judge. The half-life in obese individuals is actually more than 15 days. So it’s a drug that I guess you have to be careful with if you anticipate side effects but as I tried to show you the side effects and the metabolic ones seem to be very, very innocent.

Question: Did you find any changes in blood pressure in patients treated with rimonabant? Because we should expect a decrease in blood pressure in these patients.

Prof Rössner: What people working with anti-obesity drugs are always looking for are effects over and above those that you can achieve by weight loss only. We know here that the most pronounced ones regard the dramatic increase in HDL cholesterol, 27% that’s more than you get with a fibrate that has hypo HDL as an indication for treatment. We also know about the effects on HbA1c as regards blood pressure you get what the weight loss in itself gives but there are no good data showing you that the blood pressure itself is further reduced over and above that so far. But again this depends on what population you are looking at. As I started to outline the first trials were done with general obesity individuals who often have a slight blood pressure elevation, then those with dyslipidemia and diabetes. So I guess you have to do a proper trial in hypertensive patients directly to see. When this was done with , for instance, it turned out the risk with subutamine which was said to increase blood pressure in hypertensives resulted in the opposite, blood pressure went down when these patients had a better balance.

Prof Ritz: May I follow this question of Andrej Wiecek up with a second one? We know from the work of Luft and Sharma that visceral fat is an extremely rich source of all components of the rennin-angiotensin system because you see preferential reduction of the visceral fat, have there been reports on the measured component? I know that Sharma in Canada did work on this but I don’t know the results.

Prof Rössner: Now, I know about the Sharma work in Luft in Berlin but I don’t know, probably there’s work in progress because now Sanofi has set up a whole system of parallel trials looking at the various aspects but if area has any data I don’t know as of yet.

Prof Ritz: This would be of interest to the nephrologist beyond blood pressure because of course, this would be an amplifier of the renal risk.

Chairman: Are there further questions? If not I think you feel happy to be here and not any place. Thank you for your contribution and this brings this session to a close.