All right, welcome back to our last but not least session, which is on developing collaborations for management of complications and maximizing weight loss. It's my true honor to introduce our first speaker of this session, Dr. Sourav Mishra. He's the founding director of the medical weight program and assistant professor of medicine at University of North Carolina. Today he's going to be talking about combination therapy with pharmacotherapy, maximizing weight loss with endoscopic bariatric therapies or surgery. So a combination of what we've been talking so far, Dr. Mishra, please. Good afternoon and I'd like to thank all the course directors for inviting me to speak today. So I have some disclosures. During this talk, I'm going to be talking a little bit about anti-obesity medications when I'm talking about the patient cases and the rest of the disclosures are as shown. They will not have a bearing on my talk. Here are my objectives, but going straight on, we've seen multiple variations of these slides and just to kind of point out that 43% of Americans have obesity and 7.7% have severe obesity. If we were to think about it, only about 1.3% of the eligible patients have actually used anti-obesity medications or ever received anti-obesity medications. And even with the bariatric surgical procedures being at around 252,000 in 2018, only 1% of the eligible patients get surgery. We don't really have reliable estimates of how many bariatric endoscopic procedures are being done in eligible patients. So when we start thinking, why do we need to prioritize obesity management versus just treating the comorbidities? We can see a lot of the comorbidities as you see in the slide, we are already aware of. These are all caused by obesity. But when you look at the multiple other manifestations, metabolic, structural, inflammatory, degenerative, neoplastic and psychological manifestations, it's actually at last count was greater than 228 different conditions are either caused or worsened by obesity. So by treating obesity, we want to get to the bottom of all of these. So how do we go about doing it? We use a system, a obesity treatment pyramid. We've seen different iterations of this during the talks today. We start with self-directed lifestyle change at the bottom, which would be when people are trying to do diets and exercises by themselves. And if they were a part of a structured program, that would be professionally directed lifestyle change, seeing either health coaches, seeing psychologists, dietitians, and also the other structural programs. You have anti-obesity medications where the range of weight loss is between 4 to 9% weight loss. Endoscopic therapies, you have the ones which are, again, these are placebo-subtracted weight losses and about 3.2% weight loss for the air-filled balloons, going up all the way to 16% or more with endoscopic gastroplasties. And then you have a big gap where you have bariatric surgery coming in at 27 to 35% weight loss with the large efficacy gap. Now we can try to fill this efficacy gap with all these upcoming new anti-obesity medications that Dr. Kaplan has talked about. It's very exciting. I myself have been involved in a lot of these trials, and there are new ones that are also being looked at. So we might be able to get some of those things in the efficacy gap. And we have new endoscopic therapies coming up all the time. But despite all that is coming up in the future, we can start doing some things now to start filling this efficacy gap by using combinations with endoscopic therapies, anti-obesity medications. So what would be the advantages of combining a pharmacotherapy with endoscopic procedures? We can extend weight losses for short-term endoscopic therapy, like balloons, which are after removal of the balloon to try to have better long-term results, improve efficacy with long-term treatments, and increase the efficacy of these treatments so that way we can avoid more invasive therapies, such as surgical therapy, especially when it's contraindicated, where we see a fair number of patients where they might not be able to have bariatric surgery due to a major contraindication, like gastric laddices. And then we have to try to figure out other options for treatment of these patients, which use less invasive therapies and you combine them. So let's just start looking at the different ways we can use combinations. There have been a lot of discussions so far during our panel discussions about what is the right time to start anti-obesity medications with endoscopic treatments and what would have the best result. So there have not been a lot of studies, there have been very few studies which have been done and I'm trying to kind of show them schematically. This is one of the studies that was a multi-center study with inter-gastric balloon and AOMs that was done. It was, we've only seen the abstract, but we are waiting for the full paper. But what it showed was that AOM was started at the same time that the endoscopic balloon was placed. So it was one in four academic centers. And what happened was there was a weight loss which continued beyond the device removal at six months. So here, interestingly, at the time of device removal at six months, the difference in weight loss was very similar, 13.7% versus 14.2%, but 12 months out after the anti-obesity medication was started, the difference was a lot more. It was 21.4% versus 13.1%, so almost like an 8% difference in efficacy. But here, what we need to remember is it was very non-standard pharmacotherapy that was used. Metformin was the most commonly used agent, about one-sixth of them got metformin, one-sixth of them got metformin plus liraglutide, and about 10% of them got metformin with naltrexone and bupropion combination, also called Contrave. So it is an atypical combination of medications and metformin, although I use it in my practice and it's a great medication, it's an off-label use for anti-obesity therapy. Another way of combining would possibly be where an anti-obesity medication is started when the device is taken out. Again, there are not a lot of studies that have looked at this strategy, but this would be a rational strategy to use also when you're having gastric balloons. The third strategy, what about having it when the device is in and when the device is taken out, you stop the anti-obesity medication. This was actually done in the Middle East in one of the trials where they used liraglutide, which was started along with the gastric balloon. And when the balloon was removed, the liraglutide was stopped. As you can see, there was great weight loss with the combination at six months where it increased the weight loss by about eight kilograms with the device. But then there was weight regain and one year out, the difference was not significant. So overall, this might not be the best strategy if you're thinking of durable weight loss when we are trying to use anti-obesity medication. So if we were to use it, we would either use it after the device was removed or use it all the way through and continue it after the device is removed. What about combining it with long-term endoscopic treatments? So the device is in or if the procedure is done like a gastroplasty is performed and then you start the medication at that point, you would expect that this approach would give better weight loss and would continue. But again, there were not too many studies that looked at this. They did have, however, look at a different model. This is a study from three centers in Brazil where they started with endoscopic sleeve gastroplasty and about five months later, they were given liraglutide. Now, the liraglutide that was started was started at a low dose and they were gradually increasing the dose, how much of it was tolerated and they stopped there. So it was, again, not standard therapy. Not all of them got to three milligrams, but it was started about five months later. There are some advantages to this technique or this strategy because if you're going to have some GI side effects of an endoscopic procedure, you wouldn't be starting the medication with liraglutide, which can also increase nausea, vomiting at the same time that the endoscopic procedure is performed, but delayed by some time, let recovery occur and then put the medication in place. So here they saw a 20.5% weight loss with the endoscopic sleeve gastroplasty alone, and there was about a 4% increased weight loss by adding the liraglutide. This was at 12 months. So the liraglutide was on for about seven months out of that. So we talked about how for endoscopic therapies, we can improve the efficacy by adding pharmacotherapy, and why use it in bariatric surgery when we are saying that the average weight loss is 27 to 35%. So to be able to understand that, we have to understand what the phases of weight loss with bariatric surgery are. After surgery, you have the initial weight loss coming down to a nadir weight, and that is usually achieved at a median of about two years after gastric bypass surgery. It is different with the sleeve gastrectomy, but for example, let's use gastric bypass surgery here, and it's about a median of two years after that. But then there is a weight regain phase, and that happens one to five years after the nadir weight has been achieved. So you can think of it as three phases, phase one, where there's weight loss, phase two, where there's some weight regain, and then there's phase three, which is stabilization. But when we are looking at patients who are having inadequate weight loss, and that's primary, so-called primary failure of surgery, you have a weight graph where they don't achieve a good nadir weight in these cases. So let's understand what that actually means. A group cohort of about 10 centers performing gastric bypass surgery was published in JAMA in 2018. It is a great paper, which kind of looks at the nadir weight loss, and when it was happening, it happened around two years after gastric bypass surgery. The median weight loss for them was about 37.4%, and this is the weight distribution at Mass General Hospital by Dr. Kaplan's group. And as you can see, there is a nice bell-shaped curve of weight loss when you do it in percentage weight loss. As you can see, the different colors make up different BMI, so it didn't really matter what BMI, and it was not that better response was there in a higher BMI or lower BMI. They were very nicely equally distributed. But you can also see that on the left side, where I've shaded red, these patients achieve less than 20% weight loss. Even though the median weight loss in this study was about 39%, and most studies is 37 to 39% at Nader, about 10% was 10 to 15% of the patients achieve less than 20% weight loss. So that would be what is called as primary failure. And the other kind is when there is excess of weight regain, which is also called a secondary failure, where it's phase two or phase three. Here the patients are able to achieve a good Nader weight loss, but then have weight regain. There's always been a lot of concern about what exactly is excessive weight regain. And again, this study does the same study that we had talked about earlier did kind of define that criteria. It was a prospective cohort of 1700 adults, status post gastric bypass. And in that, they saw that once a 20% weight regain threshold is hit, then the outcomes become much worse for diabetes, physical functioning and multiple other comorbidities. But when you look at the median weight regains after Nader weight has been achieved, at one year, it's about 9.5%. At three years, it's about 22.5%. Five years is 26.8%. As you can see, even at three years, the median weight loss is crossing the 20% threshold. And at five years, a lot more patients are crossing the 20% regain threshold. So all of these patients will need some kind of additional help to be able to improve their diabetes and physical functioning. And there are multiple causes for the excessive weight regain. And the rest of the session will probably be covering some of those endoscopic options for patients who are having anatomic changes after a gastric bypass, like staple and breakdowns, gastro-gastric fistulas, pouch enlargements after a gastric bypass, enlarged gastrointestinal anastomosis. These are all anatomical changes, but we also have maladaptive lifestyle patterns that can develop later on after surgery. Post-operative addition of medications which cause weight gain, we see that a lot, especially psychiatric medications. Post-operative hypoglycemia can cause some of this weight regain also. And then what about the long-term weight regain? If you look at the Swedish obesity subject study, the green line is gastric bypass. You can see that the weight regain is gradual, but it continues until 10 years. So what does this actually mean? What is happening here? Now, for this, we need to understand the physiology of the weight trajectories in normal life. So what we're seeing here is after surgery, there's some weight loss, and then the weight tends to gradually go up. That's the perceived weight regain after surgery. But when we think about it, the predicted weight trajectory is actually a slow gain of weight during that phase in life. So the actual weight loss is still preserved, but there is a perceived weight regain after surgery when you follow them out for 10 years or more. So when we look at the data for a combination of bariatric surgery with anti-obesity agents, there are no prospective trials which have been published apart from two that were done at UK and Italy, but those have not been published yet. We just see them in clinicaltrials.gov. The study that Dr. Kaplan talked about, the Gravita study, was designed to look at diabetes outcomes, but also gives us some information about the weight loss outcomes. There are a total of six retrospective analysis of which only four of them had more than 30 patients. Here, the first one that had come out was one which had RYGB and gastric band patients, only 65 of them. Phentermine and phentermine topiramate combination was used. Very short study, only 90 days results. So we can't really understand what the long-term outcomes would be. More recent studies from the Cleveland Clinic, there were about 209 patients. Weight loss was looked at 12 months after starting the anti-obesity medication treatment. So this is a reasonable study to kind of guide us in the absence of prospective studies. RYGB, gastric bypass, gastric bands, sleeve gastrectomy were all included, and the only FDA approved anti-obesity medications were used in this study. Again, 37% lost 5% body weight. About 14% lost about 10% of that body weight. And what they found interestingly was RYGB and gastric banding patients seem to lose more weight than sleeve gastrectomy patients. And the data on combination of the surgery with anti-obesity medications was also reported from Mass General Hospital in Cornell. Here, there were 319 patients in this study. So there's, again, weight loss at 12 months was looked at. Most of the patients had RYGB and gastric bypass, and a few of them had sleeve gastrectomy. But here, there was substantial off-label anti-obesity medication use. The topiramate, metformin, zonisamide, all of them were used, again, in an off-label fashion because both these clinics specialize in anti-obesity medication use. The 54% of the patients lost about 5% of their body weight, and 30% of the patients lost 10% of their body weight, and about 16% of the patients lost 15% of their body weight. So relatively good results for what we would expect with anti-obesity medication treatments. And there was a retrospective study from Canada which looked, again, at a mixture of surgeries. But here, liraglutide 3.4 milligrams was the only agent that was used. Here, they showed about 5.5% weight loss at eight months on an average, and of which 42% lost at least 5% of the body weight, and 16% lost about 10% of their body weight. So this is somewhat similar, somewhat comparable to what was seen with the Gravita study. So how do we use a strategy to combine therapies for improved outcomes? I won't go into the mechanisms of how the different medications work. Dr. Kaplan had covered that, and Dr. Giropinio had covered how the different endoscopic devices work. What I'm going to talk about is how do we put these together? Mechanisms of action of therapies can overlap quite a bit. You can have significant overlap, partial overlap, or a little bit of an overlap. And why this is important is if there's no overlap at all, and there's no complementarity, you have additive effects. And you can have synergy also, if you have some complement, some of the pathways that are affected are complementary, and there's no overlap, you can have synergy. And also, you can have partial additivity or no enhancement. To just look at the examples, we have some examples in the anti-obesity medication realm, and fentramine and topiramate is one of that, where you can buy each one of them 4.4 and 4.2% overall weight loss, but when you combine it, you have about 8.4% weight loss. With synergy, this is canagliflozin, which is an SGLT2 inhibitor. Again, it's not FDA approved for weight loss, and this combination was studied, but it's only a proof of concept. They were combining with fentramine, and as you can see, both these medications, when combined, and you can get a synergistic response. On the other hand, you have agents like oralistat and sibutramine. When you combine them, you really don't get much of additivity, and it's probably because of a lot of overlap in the mechanisms. Although, we look at the molecular mechanisms and not a lot of overlap, but we don't completely understand how these medications work together. So, in this case, there was no additional weight loss. So, how do you start and adjust the anti-obesity medications? Dr. Kaplan had talked a little bit about this. You would think of the contraindication and acceptability of the side effect profile, cost to the patient. You would look at the additional benefits outside weight loss that the drug would cause for them, and mechanism of action. Much more important, as we understand more of the mechanisms of action of the endoscopic therapies, trying to use this in the drug choice would be helpful. This is just what we... Dr. Kaplan had already shown one of this where he kind of talked about how every anti-obesity medication therapy does have this distribution of weight loss. So, if you're going to be looking at the distribution of weight loss, you would start the drug therapy. If it's less than 5% weight loss, you would stop it. If you have a response towards the right end of the curve, then you would continue the medication by itself. And if it's somewhere in between, it's between 5% to 10% weight loss, you can continue and add another drug and add another therapy. So, these are examples of patients I have seen. There's a 44-year-old woman, 10 months post-sleeve gastrectomy. Her initial pre-op weight was BMI was 50, and her BMI was 43.6, and then she had regained weight. Another 43% of her last weight was regained, so when she came to see me. We use comprehensive lifestyle therapies, Metformin, Phentermine, GLP-1 agonist. We had put them on sequentially, and the weight loss to date is about 20% from the time of presentation. The second one, a second patient is a 70-year-old post-4 years post-RYGB. Pre-op, BMI was 38.5, natal BMI was 25. Initial weight loss was about 36%, which is really good for a gastric bypass, but then she regained about 35% of her last weight, and that's where she presented. After that, we started lifestyle interventions and treated her depression with bupropion, an example of using other agents which affect other comorbidities or other reasons for using it apart from weight, and used off-label topiramate, and weight loss with the medical therapy was about 13%. She's close to the weight where she was at her natal. This is the third patient. Pre-operative BMI was 53.5, natal BMI was 22.8. Again, she was treated for breast cancer, so that's the reason why natal BMI dropped so much, and initial weight loss was about 58.6%, and then she had 63% weight regain. She was also treated with psychiatric medication, so we modified a psychiatric medication regimen, started metformin, and 28% weight loss just with that kind of intervention. Here, we're combining medications with RYGB and getting really good results after the stabilization. This is just a slide that's out of place, but the take-home points, there's a pressing need for more efficacious therapies to address obesity, and we have, by combining anti-obesity medications with endoscopic or surgical therapies, we are able to multiply the ability to achieve better outcomes with the present tools, and when we use pharmacotherapy combinations, we have to pay attention to the mechanisms of action so that the combinations can have synergy with the underlying procedure. And there is heterogeneity of response to any therapy for obesity, and we have to incorporate strategies that allow this heterogeneity to be used, and that way, we can allow the best outcomes. I think that brings me to the end of my talk. Thank you.

combination therapy

anti-obesity medications

endoscopic bariatric therapies

surgery

weight loss

obesity management