OMTF Obesity Pharmacotherapy Update

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I'm recording the session incidentally and we will share it afterwards with all participants and with all comms members. So these webinars will take place regularly, the last Tuesday of every month, except for the two months in the summer when nobody will be about, so we have to have a rest and a break. And so we have topics already agreed until June.

We will keep communicating with you regularly and updating you on those topics. So one of the key points is, please share the information with your colleagues within your collaborating centre because these are open to anybody who works in your team. They may be of interest to anybody in your department or anybody working with you, so please do share the invitation and the information about them so that we can begin to increase the number of people within the comms that participate.

So really, this is an informal setting. You can ask questions whenever the Q&A session starts and you can post them in the chat throughout the presentations. So we're going to start today with our dear friend, Dror Dikker, who is the co-chair of the Obesity Management Task Force.

He has been running a collaborating centre for many, many years. He's the current president of the European Federation of Internal Medicine. He's, as you know, the president of the Israeli Society for the Study of Obesity.

He's running his own internal medicine department at his university hospital in Israel. And most of you know him very well already, but I feel the need to give an introduction like that. So I'm going to hand the floor to you, Dror, if you could share your slides and start whenever you're ready to give your overview and update on pharmacotherapy for adults.

The floor is yours. And thank you everyone for your attention. So thank you very much, Ian.

It's very nice to see you all, even if it's I just see you in this square, this little square. I hope to see you everyone. I hope to see everyone in May.

So I think it's a very, very important initiative and I hope we can all learn. So I want to talk today on the frame of anti-obesity medication. Here are my conflict of interest and I don't have conflict of interest regarding this talk.

So we know that the control of appetite is really including three parts. The first part is the homostatic eating, eating for hunger, which is controlled by the satiety hormone GFP1, PYY, eczema modulin, etc. And the hunger hormone GERD.

The second part is the hedonic eating, eating for pleasure, which is controlled by the dopamine and the opioid and cannabinoid system. And the third part is the executive function when we're deciding to eat or stop eating. And this is a higher level of cognition, mainly in the frontal lobe.

So this is from a very interesting and very important new publication in our European Journal of Eternal Medicine, wrote by Nick Finner, describing future medication of obesity. And we can all really learn from this very complicated... You're muted, Dror. Okay.

Now you hear me? You hear? Okay. So the control of this system is, as we saw, controlled by leptin, insulin, and the hormone from the gut. And also the vagal nerve contribute to this control and amylin.

And I will relate vagal nerve and amylin later in my talk. So we also know that in the baseline of people with obesity, there is lower response of this satiety hormone. And from this very early study, we can see that after test meal, people with obesity have much lower PYY compared to leaner patients.

And people with obesity have much lower GLP-1 compared to leaner patients, meaning this is a physiological malfunction of people with obesity. Now, we know that when we are losing weight, we are really increasing the hunger hormone, the ghrelin hormone, and we are decreasing the satiety hormone, and this leads to increased hunger. We also decrease the energy expenditure, and this creates the energy gap.

And this is also leads to this effect of weight regain, meaning that we are hungrier, and we are excreting much less calorie. And that's the reason that physiological mechanism is causing us to regain weight after weight loss. So that is the main reason for my honest opinion that using all other systems, meaning like physical activity, very low calorie diet, are effective until the physiological mechanism gets into.

And then we see even in a very effective mode of very low calorie diet, we see weight regain. When we combine diet and pharmacotherapy, then we can really prevent the weight regain and maintain weight loss. And for this, this is the main reason that pharmacotherapy is helping us in controlling weight loss.

So we all know this very disappointing result, and this is results from our very recently publication on the Action.io studies that we show that if we want to see how many people achieved 10% weight loss for one year, we can see that around 14,000 participants, only 5% maintain 10% weight loss for a year. So this is the reason that it's very, very hard to maintain weight loss unless you combine pharmacotherapy. Now, if we want to really understand weight loss, we have to see which tools do we have.

So we see that in Europe, we really have fentamintopiramide, we have liraglutide, and we have bupropionaltroxone. Sorry, we have orlistat, liraglutide, and bupropionaltroxone. Those are the three medications that we have in comparison to the state.

If you want to look into mechanisms, so we know that naltroxone, bupropion, and fentamintopiramide act centrally, orlistat acts peripherally on the gut, and liraglutide acts peripherally on the gut and also in central nervous system. So I will go very, very briefly because I am sure that everyone is familiar with all the mechanisms. So orlistat is inhibitor of lipase.

In order that triglyceride will be absorbed into the bloodstream, it has to be hydrolyzed to monoglyceride. And if you prevent this hydrolysis by orlistat, you prevent the absorption of 30% of triglycerides. So we know that we have 120 milligrams, or over the country, 60 milligrams, and it prescribes three times a day for people with BMI above 27 with risk factors or above 30 without risk factors.

In fact, this is the only medication that is approved for children above 12 years old, and I hope in the future also liraglutide will be approved for adolescents. So we know that from the study of Xanthous and the Swedish type 2 diabetes study that this is very effective drug for the first year, and even after four years of treating with orlistat, we see the difference between those who took the medication and the control, and still in favor of orlistat. We also learned that the 10% weight loss, sorry, 10% weight loss is around 30% in the type 2 diabetes and 41% in the Xanthous study.

The side effects are very, very well known. It's gastrointestinal side effects and really mainly oily spoils, and this is the reason that many patients do not like to take this medication. The other medication is naltroxone bupropion, the combination of these two drugs that's called Contrave or Mycinbineurope.

This acts on bupropion, acts on the POMAC that caused release of alpha MSH that activated MC4 receptor, and we know that there is a negative feedback by activation of beta-endorphin auto-inhibitory loop, and when we combined it with naltroxone, this is blocked by naltroxone, so the combination of bupropion and naltroxone increased the alpha MSH that activated MC4 receptor, leading to satiety and energy expenditure. We see here the prescription. We have two dosages, 8 mg of naltroxone or 19 mg of bupropion or 32 mg of naltroxone, 360 mg of bupropion, and you can see also the effect on weight loss that is significantly better than the control in the non-diabetic patient and in the diabetic patient.

Again, if you look on the percentage of 10% weight loss, 28% achieved 10% weight loss, and in the diabetic cohort, 18%, which is very, very impressive results, had 10% weight loss. Here, we have much more side effects, and we have to take it into account when we prescribe this medication. There is a risk of higher blood pressure and some psychiatric disorders that we have to take into account when we prescribe it.

More side effects are relating to gastrointestinal side effects. The third medication is iraglutide 3.0 mg, Ascenda. We know that this is the hormone that is secreting by the L-cells from the gut.

The only problem with this wonderful hormone is that the T-half is 1.5 to 2 milliliters. Then, when we are changing one place in the chain and adding residue of 60 fatty acids, we can really increase the T-half to 13 hours. We also know that the effects are increasing satiety and fullness, and increasing insulin secretion, decreasing glucagon secretion, reducing gastric acid, and reducing gastric emptying.

All is in favor of improving metabolic indices and reducing hunger and weight. GLP-1 is activating the GABA receptor, which affects the NPY nucleus, inhibits the NPY nucleus, and activates the POMAC nucleus again. The end result is increasing satiety and reducing hunger.

This leads to very wide scale studies that show us reduction in weight, a very impressive reduction in weight, compared to the control. In the best study in this area, the scale maintenance study, they achieved, if you add 6 to 6.2 percent, they achieved 12.2 percent compared to 6.2 percent in the control. Very recent, there were two other publications from the scale program, the scale insulin, that showed us that there was a reduction of 5.8 percent of weight compared to 1.5 percent in diabetic patients, and the scale IBT that reduced the weight 7.5 percent compared to 4 percent, and I will relate to this study later.

Again, if we look on the categorical weight loss, we can see that 10 percent, nearly all the studies showed us that 25, 24, 25 percent of all the cohort reduced 10 percent or more, which is a very nice result. So, if we want to summarize the effect, we can see here the weight results and the effects on the risk factors. Now, the side effects, we can see that most of the side effects, as we know with GLP-1 analog, relate to gastrointestinal adverse events.

There was a reduction in MACE event, but it didn't reach significant value, but we didn't see any harm. Of course, in every massive reduction in weight, there is Goldberger disease, increase in Goldberger disease, which was numerical imbalance. Acute pancreatitis, as in the leader, there was not increase until the level of 1.8 milligram, and there was numerical imbalance observed in line with level for arachnotype 1.8 milligram.

Regarding neoplasm, the rate similar to placebo, no imbalance in over malignancies. There was numerical imbalance in breast cancer. One of the thought that women that reduce the weights can track easily the tumors, but we didn't see this in other studies.

And no adverse event, the rates were similar to placebo. Now, if we look on all the medication that we have, again, in the targets of 10% weight loss, we can see that the GLP-1 deraglutide had 33% compared to other medication around 25, 22, or 48%. Now, in a very, very recent publication in The Lancet, and I really recommend everyone to read this paper, because this paper really summarized all what we know on pharmacotherapy for obesity, and they compare the effectiveness of this pharmacotherapy.

We can see that if we measure certainty of evidence, and the blue one is high certainty of evidence regarding weight loss, and here it's 5% weight loss, and here is 10% weight loss, we can see that there is high degree of certainty regarding 10% and 5% weight loss in fentamintopiramate, in the GLP-1 receptor agonist, and in naltrexone groupropium. When we look on the harm, okay, there is little harm in those two medications, meaning that fentamintopiramate and GLP-1 analog, and there is a high degree of gastrointestinal side effects in GLP-1 and naltrexone groupropium in other system. So, this conclusion really advised that fentamintopiramate and the GLP-1 receptor agonist are the most effective anti-obesity medication.

Now, they did very, very interesting evaluation, and they compared participant with body weight reduction 10% or more, what were the odds ratio, and discontinue due to adverse effect. So, they measure the effectiveness and the side effects, and we clearly see that GLP-1 agonist and fentamintopiramate have the highest odds ratio to cause weight loss, and regarding adverse effect, they were not the highest drug that cause stopping because of adverse effect. So, the conclusion of this evaluation was that these two compounds are the most effective compound for losing weight.

So, we really understand that the first target is to achieve weight loss, and I think that the new target is at least 10% weight loss. I think we should aim for 15% weight loss. The second target and the most difficult and most challenging target is to maintain the weight loss.

So, we did a study that we want to really measure the trajectory of different weight gain or weight loss, and in order to do so, we looked several years back, we looked on all the BMIs from 2008 to 2012, and then the index day, we looked forward what were the trajectories, and we had four trajectories. The first one were stable BMI of 30. The second one was a higher BMI of 40 that increased all the time in these five years.

The third one were increased weight and then decreased weight, and the fourth one was decreasing weight and then regained weight, and you can see the percentage of these trajectories, and we measured the mortality of these four trajectories, and we compared the mortality to the stable BMI of 30, and to our very much surprised, what we found is that if you have a high stable BMI, meaning 40, and you are increasing the weight slightly in these five years, you still have 33 percent higher mortality than stable BMI of 30, and you still have above 50 percent higher mortality in these two trajectories, increasing, increasing, and decreasing, increasing, meaning that stable weight is crucial for health, and maintaining weight loss should be one of the major targets of treating obesity. So, as I told you before, using pharmacotherapy, in this case, GLP-1, analog liraglutat 3.0 milligram, can stabilize the weight loss, and as we see here, for three years. When you stop taking the medication, you are, again, regained weight.

Now, this study, the SCALE-IBT study, is a very, very interesting, very important, to my honest opinion, study, because we can see that if you combine liraglutide with IBT, intensive behavioral treatment, meaning 21 counseling visits, you can really stabilize the weight loss, and it's very interesting that to see that those who participate in all, in all the 21 sessions, and use liraglutide, reach 14 percent weight loss, and maintain this 14 percent weight loss. What we also learned in the sub-study of this study is that the effect of liraglutide on hunger, fullness, and perception of food is really very prominent until the week of 28. From the 28th week, these differences become non-significant anymore, meaning the central effect of liraglutide is really meaningful in the beginning of treatment, and I'm sure you are, you have patients that really felt that the effect of liraglutide really subsides with time, which is true, according to this study, but the effect of weight loss stabilization is not subsiding.

So, we have to take it into account and bear in our mind that, meaning the feeling of the reducing of hunger, fullness, is subsiding, but the metabolic effect and the weight effect is still there until you stop the medication, as you see it here. Another study with liraglutide is a very recent study was published in the New England, and see, and you can see it again when you compare it to very intense physical activity, when you combine liraglutide, very intense physical activity, you are really consolidate the weight loss, but even just liraglutide, you still consolidate the weight loss. So, combined method, meaning diet, physical activity, and pharmacotherapy can help us to maintain weight loss.

This is what we have to do. Now, very briefly, I want to really touch upon the future anti-obesity medication treatment. I will start with the semaglutide, which is the future medication.

So, semaglutide really acts directly and indirectly in several parts in the brain, and when you compare it to liraglutide, you can see that there is increased enhancement in the area of hypothalamus, archaic nucleus, and in area of prostate. So, there is difference between semaglutide and liraglutide in affecting several parts in the brain. So, we have, again, a very vast program which goes step between step one until eight, and the results are really, really remarkable.

We can see here that we can achieve between 70 to 80 percent weight loss in different studies, and we can achieve nearly 70 or 80 percent weight loss, 10 percent weight loss, meaning the majority of patients losing 10 percent of weight, which is very, very impressive. The other combination is the combination of GLP-1 and GIP, and we can see here in diabetic patients, again, a very impressive reduction of weight in this very difficult cohort to reduce weight. So, the combination of GLP-1 and GIP are very, very effective in weight loss, and now there is a new program for people without diabetes, the Serumman program, and it will be very, very interesting to see this combination in obese patients without diabetes.

The third treatment is the amylin. Amylin is a neuroendocrine peptide that is excreted with insulin from the pancreatic beta cells, and it's involved in appetite regulation and satiety signal. So, now we have a phase two study at 26 weeks of several degree of amylin, and we can see that the highest degree or highest dose of amylin can lead to 11 percent weight loss compared to 9 percent weight loss with liraglutide.

And we can also see, and you can see here the effect on uncontrolled eating, emotional eating, and cognitive restraint, but we also can see that liraglutide is very effective compared to amylin. So, we can really appreciate the effect of liraglutide on this measurement, but also to acknowledge the effect of amylin on weight loss and controlled eating. The next compound is combination of amylin with semaglutide, and this is again a very early phase, and for the first 20 weeks, we can see dramatically weight loss that reached 17 percent in the highest combination after 20 weeks.

And the last one is setmelanotide. This is not a study compound. This is a compound that we can use for monogenic obesity, meaning those who have genetic disturbances in the POMAC, in the leptin receptor, in the PCSK1, and in leptin itself.

We know that in order to excrete alpha MSH that will activate MC4 receptor, we need a leptin, we need leptin receptor, we need the POMAC, and we need PCSK1 to cleavage the alpha MSH in order that the alpha MSH could excrete from POMAC. So, if we have genetic disturbances in every part of this chain, we won't have enough alpha MSH. So, setmelanotide really bypasses these disturbances and activates alpha MSH directly.

So, we know from this publication that giving setmelanotide to people with POMAC or PCSK1 genetic mutation or leptin receptor really achieved a dramatic weight loss, as we can learn from these results. 80 percent lost more than 10 percent, and the mean weight percent were for the POMAC 25 percent and for the leptin receptor genetic disturbances 12.5 percent weight loss reduction. Of course, it comes with some side effects, mainly injection side reaction and skin hyperpigmentation.

So, by presenting you the future and very near future, I hope, we can really be very optimistic on our ability to treat obesity in the near future. And I want to thank you for listening, and I will answer your question now or later. Thank you very much.

Thank you very much, Dror. That was an excellent summary for everybody, I think. So, you can either ask questions in the chat, although I don't see any in there yet, but if anyone has any questions, all you need to do is raise your hand, unmute yourself and speak, we'll give you a minute or two to, or a moment or two to think about any questions, but otherwise we shall, we shall move on.

I would, I would have one, one question coming in already from Andrea from Spain. Andrea, could you just unmute and ask away? Yes, thank you very much. Very, very nice talk.

I have one question, said melanotype is approved for specific mutations, or for instance, if we have a normal patient with obesity and we detect a mutation of any kind in this gene, we can use this drug or is limited to specific mutations? So, thank you, Andrea. It's a very good question, but now, at least in my country, since it's a very, very expensive drug, and it was proven only for this specific mutation, it's prescribed for this specific mutation, but we are now in the beginning of studies that we see much more mutation and treat much more mutation than just these four mutations. So, I expect that in the future, after we will study it, and if it will be found really efficient for other mutations, we could use it, but for now, I think it's prescribed only for this four mutations.

Thank you. Thanks, Dr. Ror. The next question goes to Brij.

Yeah, thank you, Dr. Ror, for a very nice presentation. Just wanted to know, do you have any experience with oral semaglutide for weight loss in non-diabetes patients? Because it does cause weight loss in diabetes patients, but we don't have any data on that. Yeah.

So, the problem is that, I don't know if you have this problem, but we have a huge problem in Israel regarding semaglutide, because we have huge off-label treatment of semaglutide in non-diabetic patients, and this is wrong. So, of course, rebalances of oral semaglutide is questionable if it's helping to lose weight. As we learned from the studies, the effect on weight on oral semaglutide is not so good as the subcutaneous.

Yes. In a way, I think a new study will begin in the future with higher dose of oral semaglutide for treating obesity and non-diabetic obesity, but this will be a higher dose. So, the dose today is not really effective for meaningful weight loss.

Okay, thank you. Because we just, in India, only oral is available. Injectable is not available.

So, you know, here also we see now it is going to have off-level use for weight loss also. Yeah, I don't think it's so effective. Thank you.

Thanks, Jor. Thanks, Birj, for the question. And one more hand is from Liesbeth van Rossum from the Netherlands.

Yeah, thank you so much. Fantastic presentation, Jor. I was wondering about your clinical experience, or maybe from others.

Of course, we know that I think you stressed the weight maintenance, the weight loss maintenance, which is really important. I totally agree. And I was wondering, we know from the studies for GLP-1, there are like three years people have to be on a medication and once you get the weight regained.

Same as for naltrexonebiproprion, it's one year if you stop it, weight regain. So, we think you should take it for all the time, thinking of the mechanism of dysregulation of the hormones. But I was wondering if you have really substantial weight loss, and sometimes do you have some patients who use a lower dose because of cost aspects, because they pay it themselves sometimes.

What's your experience? Do you think we can adjust? And are you aware maybe of any studies being scheduled for that, to use lower dose for weight maintenance phase? So, after the phase, because maybe part of the hormonal system will recover after substantial weight loss. Yeah, it's a great question. So, I think that the two targets are two different physiological effects, meaning that weight loss is one effect, or one physiological effect, and weight maintenance is another physiological effect.

Many people are not agree with me, but I have to tell you that I use lower dosage for maintenance, for economical, and also for the compliance of patients. And I have to say that I learned it from the patient themselves. They're coming back to me and they say, look, instead of 3.0 milligram, I use 1.8, and I have the same reaction.

And I listened to them and I started to do it by myself. So, I think also for economical consideration, but also for physiological, because if you reduce the amount, if you reduce the dosage, so you have much less side effects. So, I think for weight loss, you need higher dosage.

And for weight maintenance, maybe in some people, you can use lower dosage, because for maintaining the weight loss, you don't have such a high level. You don't have to have such a high level of GLP-1. In contrast to what I said now, if you reduce the weight, the GLP-1 level also is reduced.

So, you have less GLP-1 when you are reducing the weight. So, the logic will be that you have to give higher level of GLP-1 in order to maintain the weight loss, but this is not happening in real life. So, in real life, I'm successful in maintaining weight loss in some people in much lower dose, but it's trial and error and you have to really use it.

Some people come to me and said, look, the effect is subsiding and I don't want to take the medication. So, what we are using to do is to stop the medication and start to build the dosage again after one to two weeks. And sometimes it's very successful because maybe we are retraining the system.

So, in answering your question, I think it's logical to reduce the dosage in maintenance because it's lifelong. And what very important sentence that I'm telling my patients in the beginning is that obesity is a chronic disease and this treatment will be lifelong. But I also said that in the future we will have oral medication, we will have weekly medication, maybe monthly medication, so the treatment will be easier, but this is lifelong.

Yeah, thank you so much. And I had the same impression at older age, like 70 plus or so, that they sometimes do very well on very low dosages that they also consider a side effect. So, it's one thing.

I agree. I have the same. Yeah, I think you also just answered the question in the chat, which was due to the risk of weight regain, do the patients need to be on laryngitis or semaglutide indefinitely? But I think you answered that nicely in your final sentence there.

We have a couple more hands up. I think we have time just for a couple of comments and questions before we move on to the second speaker. So, do you want to respond, to ask your question and then Andrea after that.

Yeah, just a quick extension of what Lisbeth asked. You know, we have to continue this to keep this set point at a lower level to sustain body weight. There were some studies in the past which showed that if you sustain body weight, weight loss for five to seven years, possibly the body's set point will come settle down at a lower level and you may be able to discontinue medication.

Any comments on that? Yeah, I don't know if to discontinue medication, but I absolutely agree that we are training the set point to a lower level. You can see it on bariatric surgery. So, I think it's a very new area and we have to learn about it.

But I agree the assumption that after several years we can really train the set point and of course, if people are really keeping a healthy lifestyle to lower set points. So, I agree. Thank you, George.

Thank you, Brij. And Andrea, I think this will be our last question or comment before we move on. Thank you.

It will be brief. You explained that when you lose weight, your GLP-1 levels also drop and that's a metabolic adaptation, but also dopamine deficiency occurs. Do you have experience or what is your opinion on using fluoxetine also for the reward circuit of these patients or the combination? I have good experience with combining the two drugs and I would like to know your opinion on this.

I never use this one and I would like very much to learn from your experience because we are not combining these two medications. Okay, thanks. I noticed that Lisbeth has put a comment in the chat.

So, if anybody wants to respond to that within the chat, that would also be fantastic just so we can keep the discussion going on that side. So, thank you very much, Dror and everybody who participated in that discussion. Very nice to see it.

It seems there is a future ahead of us, which is encouraging, I think, for patients and clinicians. And is there a future also for pharmacotherapy for childhood and adolescence? We'll find out soon from Jens Christian Holm, who is the co-chair of the ESO Childhood Obesity Task Force. He's also running a big clinic in Denmark, just near Copenhagen, with many hundreds and thousands of patients over the years.

And so, Jens Christian, if it's okay with you, I give the floor to you now for your update on pharmacotherapy for the treatment of obesity in children and adolescents, which I think is a very interesting topic just now. Can you see my slides, Johan? Not yet, no. Let me just, hang on though.

I could probably need to. I just need to. I need to share.

I just need to make you a. I need to share. I think that should be better. Yeah, there they are now.

You're up now. Thank you very much. I'm up now, yes.

And then actually going into this one here. Okay. Can you see? Are they, are they large now? Are they? Not yet.

They're not yet. But I saw that you pressed the Yes, exactly. But sometimes it's a need to do it.

I think here. I'm sorry. It's all right.

It's still not large. I have a problem sometimes with this, with my computer. Nope, still not.

Can you see it on this screen? Is that okay? I mean, I can read it. I don't know if it's big enough for everybody, but. No, because you can try going to the top of screen and press on the, you know, presentation.

I've actually had this problem before. I'm very unfortunate. I'll try to unshare and then try to make one more time.

Sorry. Okay. Going there and then going.

Okay. What about this? Did that help? Not hearing it. You have to close it and then.

Yeah, I know. It's just. Before you, before you share the screen, before.

Yeah, I know. That's what I'm trying to do, but it doesn't really work. No, I'm sorry.

You can see them in the slides here. Is that right? You see? Yeah. Yeah, we can see.

Yeah, that's okay. You can try and get it full screen again, but we can, we can see if anyone has. I think you can see it.

It is not really that important. Thank you very much for that nice introduction. I would like to give some insights about pediatrics and the use of pharmacotherapy in terms of obesity and related complications.

And I think we need to start up to be aware that we are speaking about children and that children are going through growth and development and growth and development means very, very systematic changes in body composition in boys and girls. Meaning that we're not really speaking about weight loss because children are enlarging, they are climbing in height, and they're also having a high weight. And you can actually have a weight loss, even though they are increasing their weight, but reducing their fat mass percentage as exemplified by a big source of impotence in this way.

So we have some other things we need to be aware of here. And we also need to respect the fact that they are growing. So caloric restriction is not really feasible throughout the next 10 coming years during growth and development.

It has some special obstacles to pay attention to. I think it is very much important that we really acknowledge that obesity is a disease, Dror said it briefly, but I think it's extraordinarily important that we really understand obesity is a disease and that we should understand it as such and also take the responsibility as healthcare professionals of how to diagnose and differential diagnose but also treat and also include pharmacotherapy in this treatment. You can see I'm changing slides, can't you, June? So you can see I'm changing my slides? Yes, we can.

And for me, they're big enough. So I think they're okay. Yeah, thank you.

I'll just be certain about that. We also need to acknowledge the complications. We have published from our clinic, we have taken probably 5,000 patients into treatment within the last 12-13 years.

And we have published a series of publications about that, that 50% of these children with an average age exhibit pre-overt hypertension, 41% exhibit sleep apnea, 31% exhibit fatty liver disease, 28% exhibit dyslipidemia, 18% exhibit pre-diabetes. And those are only a few selected complications, but there are many more complications that in many ways harbor or actually have a huge impact on normal growth and development and then physical and mental and social thriving, which is extraordinarily problematic when you build your personality as an example. We are a club, as June just briefly said, actually since 2014, and thank you for that.

We have some inclusion criteria, not many, we just have a respect to the degree of obesity at BMI above the 99th percentile for the age and gender and an age span usually between 3 and 22 years of age. We have a series of publications of approximately more than 25 showing that we are able to reduce the degree of obesity in 65 to actually 90% of the children adolescents entering obesity treatment management. And we can constantly also reduce the degree of hypertension, steatosis, dyslipidemia, parental degree of obesity.

We reduce appetite and bullying. We increase quality of life, body self-esteem and mood as both in primary sector and secondary sector clinics. Our results are independent of a genetic risk score comprising 15 genes leading to obesity, independent upon degree of obesity and socioeconomic status, independent of familial predisposition to obesity, independent on impaired glucose tolerance and independent of disordered eating.

So this is our program and we are very much eager to combine with pharmacotherapy and we have also started that. I'll come back to that. This program is the backbone of the Danish guidelines for examination and treatment of obesity in children and adolescents.

But now I'd like to go into a more clinical based discussion because when we have all these children, we have these results that I briefly went through. We have some children that are responding very excellent to our program. They're diminishing their degree of obesity.

They are being positive in many other indices of success, quality of life and mood, etc. And we have some other patients who are actually coming to the appointments trying to meet the standards of the treatment plan equally as good, but they have much more intermediate or even poor responses to the same degree of treatment. And in my point of view, this is to be anticipated because obesity is a disease and people are different.

They have various genetic backgrounds. They have various psychosocial circumstances. So exactly those two things, genetics and psychosocial circumstances, in my point of view, major influences of how the treatment courses actually go.

So I think it's very important not to just compare children as comparing one to one, but actually understanding that they're actually behaving very much differently. And also there should be a select group probably more potentially receiving pharmacotherapy than others. Nournon has put out the press release in March last year that it was very soon to be expected to the approval for Leucotide in adolescents.

And that actually came in May 21 in Denmark based on safety and efficacy of Leucotide 3.0 milligram. And the usual things that I'll come back to with dose escalation over four to eight weeks, as you see in adulthood, as well as subcutaneous daily administration and anti-total lifestyle therapy. I'll come back to that as well.

I think Duvall has went this through very well. I am very close to some of the founders and inventors of Leuco1, Jens-Juul Holst as one example. And I asked him a few weeks, months ago, whether how it worked in the brain, and they actually do not know.

So it has very complex interactions with some of those neuropeptides that draw very beautifully shown in his previous presentation. I think that all these physiological complex interactions within the hypothalamus being both orexogenic and anoxyurectic neuropeptides are crucially important. And I very long way agree with Dror about how these physiological adaptations toward changing fat mass is very important in how to view the patient.

In our clinic, we actually put this into play with each and every patient saying that we have complex regulation in the body that actually preserves fat mass over time. And I think that was also some of the remnants of the discussion previously in this discussion. There was a safety paper some years ago showing that the safety was to be compared to adults in adolescence, so we can proceed with these findings.

And then Aaron Kelly showed this beautiful study a few years ago in 2020, Neurogeneral Medicine, showing both the anticipated effects, and also what you would call the anticipated side effects that were aligned with the findings in adults and thereby also what you could call something you could use in clinical practice. There is one thing that I like to highlight, and that is that it is said it should be an adjunct to lifestyle therapy. And I read this paper, but also read the appendix, and it is actually 93 pages.

And this is what I could find, what you can see at your bottom left side, Counseling and Health Nutrition and Physical Activity. This is actually what the paper states, how the patients receiving a leukotribe was actually counseled in terms of nutrition and physical activity. And I will just conclude, not much.

But I think this is very important, and I will also show you a slide that will show you before showing my point. The side effects are very similar to the adult population, so I'll not tie you off with this. I think you'll very much have to review this, go through this entirely.

Just say that 100% of the children or adolescents received or experienced some of these side effects and 10% of the patients actually stopped treatment due to side effects. The indications will be an adolescent 12 to 17 years, and probably an iso-BMI of 30, and or and or related complications. I think this will be a little bit clinic-based, but I think will be the official way to go.

Some degree of poor response to lifestyle treatment alone, and also an adjunct to a management, obesity management. But I think there is some problems I think that we need to identify those not much in need, but they are the safety and side effect, obviously, as an adult, that duration and cost, obviously, as also in adults. And I also think there's the question about treatment effect after termination of the treatment.

And I'm primarily speaking of a leucotribe and GOP1 now, because that is the big thing in PGI right now. The other targets also shown by Dror, I think are much less interesting. So I'm focusing on leukotribe, this talk.

The stopping rules put forward by FDA and EMA, I think is extraordinary problematic, especially in pediatrics. Because in my point of view, it should really be those patients that need the most to receive this type of therapy. And if you require a 5 or 10% weight loss, which is beneficial in many physiological systems, and also abuse and complications, but it's actually counterproductive in my point of view, because it's probably those patients with the most fiercest neuroendocrine defense of the fat mass, and thereby be more difficult achieving these 5 to 10% weight losses that actually needed the most.

I think there's some discussion here. And there's also some discussion in pediatrics, as I mentioned from the very beginning, in regards of growth and development and modulation of body composition, fat mass, lean body mass, and so on. What is a 5%? What is a 10% weight loss in pediatrics? Not that easy just to conclude out of this.

So I really think as a pediatrician and a clinician, I'm certainly focused on those patients of mine that have the most difficulty in handling, managing their obesity. I also think we will probably go into some analysis in terms of genetic risk scores and polygenic risk scores, and also what are success criteria beyond the changes in BMI and STS. We have contributed with some, I think, pretty interesting papers along the way.

This is a recent paper a year ago, where we actually showed that endogenous GLP-1 was associated with overweight obesity and also cardio metabolic risk factors in children. And I think this is interesting, because we have included these 5,000 children approximately within our clinic within the last 13 years, but we also put them into a biobank, we just rephrased, called the Hot Big Study, which is a pretty big biobank with approximately thousands of phenotypic traits for each patient, and where we have many, many repeated measurements of blood samples and dexels and blood pressures and also genetics, actually. Another paper was in a subgrouping of papers where we have identified, I think it was in this paper, there's only like 14, but I think we have 28 in total, patients carrying the MC4 receptor mutation.

And we actually treated them with the ODD-OP1 receptor agonist again here, and we actually showed that it mattered, so we can really conclude that the fully functional MC4Rs are not required in order to mediate weight loss of ODD-OP1, and it causes a significant weight loss, and it actually improved fat mass, weight circumference, and during the weight. So it's actually effective at treating monogenic obesity, and I know some of the leaders in the field actually were not aware about this before we published the study. Another study, this was the heterogeneous MC4 reabdotic carriers.

This is another study carrying only one patient, namely a homozygous GLP-1 receptor carrier, where GLP-1 actually was also efficient in providing some degree of weight loss. And I think these findings are intriguing because I think we need to sub-differentiate our patients in the future determined on various genetic backgrounds and so forth, and I think the genetic and polygenic risk scores are probably going to be important within the next 10 years or so. This is the study that I know Dror showed as well.

He showed the synergistic effects between the GLP-1 and also the what you could have called lifestyle interventions in terms of nutrition and physical activity. We see synergistic effects, which are actually seen very much in many of the studies that Dror also showed that if you combine the pharmacotherapies, you often have synergistic effects. And I think in my point of view, I like to go to hypertension.

If you go into the history of hypertension, we started out with having some very simple drugs, you could say, some dehydration drugs and some beta agonists, and then we improved our strategies with calcium antagonists and also some ACE inhibitors, thereby we actually learned to control also the more severe cases of hypertension that needed this combination therapy in order to really win over the severe cases of hypertension. I think we will face a similar story here, where our target pharmacological targets are hitting some various places, actually we do not know where in the brain most of them, and they probably work in concerto in order to promote the reductions in the fat mass that we are aiming at. So I think this was in order to put my time brief and also in order to respect the time, I think this was what I like to contribute with today.

I also have a few disclosures, so thank you very much. Thank you very much indeed, Jens Christian, that was really very interesting indeed. So I also open the floor to the participants, if you have questions, please raise your hand or put something in the chat, but you can all speak, so raising the hand works quite well.

I also have a couple of questions, if that's all right, and it's more maybe around the practical side of things, but in the previous discussions, we talked about the need to be undertaking some kind of intervention, medication in this case, indefinitely, because of the chronic disease status of obesity. Is that something that children, adolescents, parents have difficulty reconciling? And do the younger patients have more difficulty in adhering to a treatment regime that might include medication? That was many questions at a time. I will start another.

We had another problem, I think it's very interesting what you asked about that. There was a previous discussion just before my presentation, discussion about the set point, how long that lasted. I've made a PhD in fat mass regulation and neuroendocrine regulation of fat mass.

I've used many years in that field, still using time in that field, I think it's extraordinarily interesting. And I remember a study where we actually have at least eight years of experience that people are trying to recline to their former BMI if they had a higher BMI previously in life. So in my point of view, the set point discussion is intriguing, but we have not proven there's a set point.

But I think it's right. But I also think that the set point is for life. I don't think it's for eight years or 15 years.

I think it is for life. I think it's depending on how you're living your life, how you're living your life in society, your genetic makeup, and then you have chances that are more or less dependent on these two factors and also other factors. In children, I have no experience with pharmacotherapy in children.

We're starting in the adolescence from the 12 age. And I would say that our programs are designed so we have a healthcare professional control from the beginning and thereby handing over control in a care self-care model. And there pharmacotherapy has certainly a role and also quite a substantial role, I would say, but also not an entire role because we're speaking about children during growth and development.

We have these side effects. We could also argue about long-term side effects that we know nothing about right now. And we have no, not that much of an effect on appetite after termination of therapy.

Adolescents are in principle a little bit more difficult to treat due to the fact that they are going into their own control by growing up and gaining autonomous function over their own life being adults, becoming adults in transition. And thereby there is a little bit more uncertainty from coming from your parents' grips until you have sustainability. And thereby also having more challenges with obesity management that is really required, have a lot of requirements.

I think that we, our program is targeted very much direct of what I just argued about. And I think we have recently, recently success with that, but they are still a substantial, at least 15%, I would argue that we have really difficulty in handling. We have mentioned receptive patients that we have put on sick medicine as also previously discussed.

And I would, I would, I would argue that we will go into a very genetic route from now and try to diagnose, and especially the polygenic risk also, and also genetic risk also try to make a makeup of differentiation between these response patterns. But I think that it is pediatrics. It is how it always been with every disease, that it is difficulty in adolescence to make people take the medications throughout these challenging years.

And that is just a pediatric standard demand. And that is not different in obesity. We just need to take it just as, just as, just as serious in projections on these years as we do analysis with other diseases.

I don't know whether that makes sense. Yeah, yeah, very, very useful and very helpful indeed, I think for everybody. Thank you very much Jens Christian.

I'll have a couple of, I'll read out a couple of questions from the chat and then I'll open the floor to Brij, who has his hand up. So a couple of questions from Irena Althun. So firstly, she says, thanks, brilliant presentation.

How are you able to support lifestyle changes in your patients? Do you use telemedicine tools? And then a follow-up question is out of curiosity, do pediatric patients need to pay for liraglutide treatment in Denmark? So the first one, how do you support lifestyle changes? Do you use telemedicine? Thank you very much. I have invented a model called the Holbeck model of CT-OCT protocol and all that. That is, that is an integration of standard pediatric practice with obesity.

Well, how, how to, how to meet demands with these diseases that are much more strenuous than any other disease in pediatrics actually. And, and in that model, we are, we are working very much of the how to, how to, how to transform treatment responsibility from the healthcare professional onto the family, the parents, all of the adults are becoming of age. So that is something we have been working from, from the very beginning and where we have these 25 studies showing relatively robust results up to 36 months.

So that will be my initial answer. The next thing is that in Denmark, patients pay themselves for GLP-1 and that is very expensive. That's a huge problem and a huge barrier to treatment.

And that's the next thing that we have, which is extraordinarily problematic because as in every other country, we have a skewness towards obesity and lower socioeconomic status, and they are less able to pay for their medication. So that is a, that is a showstopper. I would say to some extent, we can treat the patients that can afford it.

So that's actually a minor proportion of all the patients. I think that would be the answers to these two, again, difficult questions, but also intriguing. I think the model of how to understand your own disease is like in any other disease.

If you have cancer, you need to have a perspective, how to engage, to try to counter it. And that's actually what our model is doing is promoting, it is enforcing a perspective within the patient, which is not based on motivation, because I think motivation is disqualified by understanding the disease, but instead replacing motivation with perspective, where patients understand their disease and understand what it means to tackle that disease. Thank you very much indeed.

Very, very interesting response. Thank you. Brij, I give the question to you.

Just one quick question. Where do you see the role of bariatric surgery in children with obesity? No, we do not have extended that in Denmark. We have had discussions with them several times.

The standard border in Denmark is 25 years of age. And I could probably have pushed for having children, adults, I'm sorry, from an age of 20 or 18 go into surgery, but I actually did not do it. Because 10 years ago, I think the time was immature.

Maybe now it is better, but also the surgical solutions and the implications for the rest of my life. It's just some of the surgical procedures in any way. So we have not really done it.

We have had this discussion with our surgeons several times, but never really proceeded with it. And I also think there's some problems here that are not that fundamental. But I think we will probably engage in the future.

But I think we have the problem about age, development, growth, and these gastric surgeries. Maybe in future, we'll be using more of, you know, newer molecules like injectable semaglutide and maybe the amylin analogs, which will give you results equal to bariatric surgery. Yeah, I totally agree.

I was in a conference in Washington in 1996 in March, just after the huge break in nature of Lipton. And that conference in Washington, actually, there was depictions of at least 10 of these neuropeptides that draw a field of amylin analogs. So actually got a total scene setting at 96 in Washington at that time with all these peptides.

And I think they are developing in the pharmaceutical companies now for very, very huge efforts to put into this development as Dror actually exemplified before. And I think this will move a little postponed into pediatrics due to the concerns of growth, development, and other side effects that we are really aware about in pediatrics. But I foresee a future maybe 10 or 20 years from now, where we have combinational therapy like in adults and also in beasts in general.

Thank you. Thank you very much, Jane's question, would you just mind unsharing your screen so we can go to the gallery? No, no, no problem at all. It was a nice advert for the Congress in Maastricht.

To which everybody is welcome to participate, of course. So yeah, I think that maybe brings us to the end of the session. I don't see any more raised hands or questions in the chat.

So thank you very much, everybody, for participating. I think this has been a very nice addition to the comms network to get everybody together regularly to have these discussions around hot topics. As I said at the beginning, we will hold these the last Tuesday of every month at the same time, five o'clock Central European time.

The next topic is going to be on sarcopenic obesity. So I will send information on the program for that early next week so that you have the details. And again, please share with your colleagues within your collaborating center.

This should be for anybody who is working there and who might have an interest. But we will record everything and share once we have the approval of the of the faculty for each of the for each of the sessions. So so thank you very much, everybody.

If you have any questions, you can send them to us by email, but we'll share the recording soon and we look forward to seeing you at the next comms gathering, the next comms session. So in the meantime, take care, be safe and hopefully hopefully we'll see you in person. So we'll see you in person soon.

Take care. Thank you. Bye.

Good night.