And so I'm going to take it as a jumping off point what you've heard about lifestyle therapy from both Dr. Zapovian and Dr. Kushner. Now what we know when we think about the causes of obesity is that it is a disease of modern society and there are many forces in society which seem to promote obesity, promote weight gain, promote body fat gain. And some of them are listed on this slide. And the way they appear to work is that they increase the body's desired amount of fat. Fat is highly regulated organ within the body. You lose baby fat when you're very, very young. You gain fat if you're a girl during puberty, you lose a little bit if you're a boy. You gain fat obviously during pregnancy and lose it after lactation is complete. And many people gain fat during the course of latent course of life as muscle is replaced by fat. And of course, after menopause, some women gain a lot of fat. But beyond that, even though there's a normal regulation of fat, there's an abnormal regulation of fat that occurs in response to these and other forces, including pollution and other things in the modern environment. And in order to fix the problem of obesity, however you do it, you've got to reduce that drive toward accumulating more fat, that drive toward having more fat that's associated with obesity. One way to think about it is obesity is a little like other normal ways of gaining fat or normal drives to gain fat, except that it's abnormal. So where the physiology of fat gain during pregnancy is normal, appropriate, and also autonomic. People don't have to voluntarily or purposefully gain that fat. In obesity, it's autonomic. It is not purposeful, but it is not normal either. So in order to reduce the abnormal amount of excess fat, the body's desire to have too much excess fat, the first thing we do is of course, lifestyle modification. And it works best if the lifestyle modification is directly targeted at the things that in any given individual are likely to have caused the weight gain, the fat gain in the first place. And some of those are shown right here. We also know at the other extreme of intervention, bariatric surgery causes dramatic weight loss. And we now know through studies by multiple groups over the last 20 years, that it works by decreasing the body's target fat mass. It actually reverses these upward forces that I'm showing on this slide. Now drugs, when they work effectively, also do the same thing, but you see here, the arrows are variable in size because different medications in any given individual will work differently as I'll show you in a few minutes. But when they work, they decrease body fat and therefore body weight autonomically, meaning that it occurs without direct intervention, voluntary intervention by the patient who's receiving the medications. That's not to say that the combination of medications and lifestyle isn't better than medications alone. That's been demonstrated numerous times, but they're independent, they're complimentary. It's almost like when you add a medication to lifestyle, you're adding two different therapies. This will be important at the end of the talk. Now we know that obesity is grossly undertreated from a medical perspective, 46% of US adults meet FDA recommendations and society guidelines for anti-obesity pharmacotherapy, which include having a BMI over 30 or a BMI over 27 with a significant comorbidity. And yet only less than half a percent are currently treated with anti-obesity medications of any sort. And you can see here, as you compare obesity with diabetes, you can see the percentage of the population with obesity versus type two diabetes from a study that was published five years ago in obesity. And you can see the percentage that received therapy shown in blue, 1% or less than 1% of eligible adults received anti-obesity therapy, whereas 86% of eligible adults received anti-type two diabetes therapy. Now the FDA approved medications for obesity treatment, what we call anti-obesity medications or AOMs for the rest of this talk, include Phentermine, which has been around since 1959. It's an adrenergic agent, Orlistat, which is a pancreatic and intestinal lipase inhibitor. So it interferes with the intestinal absorption of fats, the combination of Phentermine and Topiramate, which is sold under the brand name Qsimia, Topiramate being a GABAergic compound, Naltrexone and Bupropion combination, Naltrexone is a site dependent, meaning a regionally dependent inhibitor of opiates and Bupropion is a dopaminergic agent used also under the name Welbutrin and Zyban used for smoking cessation and for depression. Liraglutide sold under the name Saxenda is a drug that is a GLP-1 agonist and set melanotide is the most recently approved drug for treating obesity that's targeted for the small number of people who have either monogenic or syndromic obesity that affects the MC4, the melanocortin 4 receptor pathway. Yet the indications for AOMs, as I've already indicated, are BMI dependent, at least they are at the current time. Now, if you look at the different mechanisms, I already talked about that, and you think about the drugs that we use in common clinical practice, we use virtually all the drugs that are approved in common clinical practice, but we also use zonisamide, which is another gamma receptor agonist we sometimes use because of reimbursement issues, GLP-1 agonists that are not formally approved for that process, like dulaglutide. We're also beginning to use somaglutide, Ozempic is approved by the FDA at lower doses for the treatment of type 2 diabetes, but it does have significant weight losing effects and so has begun to be used in this way. We also use a great deal of metformin, not a terribly powerful drug, but a drug that improves metabolic function as well as having modest weight loss effects. Now, if you look at the average weight loss of these different medications, they're shown on this slide, phentermine about 5% to 7% or a little bit less, phentermine and topiramate about 7% to 9%, bupropion and naltrexone about 4.5% to 6%, glaglutide 7.5% to 9% and setmelanotide, huge amounts of weight loss, but in a very, very selected genetically and syndromically selected population. But more important than the average weight loss is the fact that for every one of these therapies, there's an enormous patient to patient variation in response. So what you see here is the response to a low carbohydrate diet. And by the way, the same thing is seen with a low fat diet, same thing you see with a balanced diet. And with a low carbohydrate diet, some people to the left of the vertical black bar here actually exhibit weight gain. Most people exhibit a modest amount of weight loss and a small percentage of people on the right exhibit an enormous amount of weight loss in the range of what you see with bariatric surgery. If you look at drugs, this is loraglutide again, this again, some people will see weight gain on loraglutide. These data are from the registration trial, the trials that allowed the FDA to approve the drug. Even in those trials, some people gained weight on the drug. Some people gained, lost rather bariatric levels of weight. And most people lost again between 7% and 10% of their weight. If you look at the duodenal liner device, you can see the distribution of weight loss. Again, we're not talking about diabetes in this particular experiment where you can see the weight loss is shifted to the right. Nobody was gaining weight in this small study, but the distribution looks the same in all three categories. And you see the same thing with bariatric surgery. Obviously there's much more weight loss on average, but the standard deviation in each of these curves is between 10 and 12%. The variability is the same regardless of the type of intervention and regardless of the fact that the average effect of the intervention varies quite dramatically from in the case of diets around 5%, 6% to the case of bariatric surgery about 30%, 35%. Now, if you look at the response to medications in the case of loraglutide, I've already shown you some data. Here's another data set from loraglutide, but it's true of every medication that's been looked at. On this slide, phentermine, propionaltrexone, which is Contre, or castorine, which recently has taken off the market. But the point here is that it doesn't matter which therapy or which drug, you see the same type of broad distribution. So as a result, the pharmacology algorithm that we typically use is we start with what we feel is an appropriate anti-obesity medication using safe use protocols. We give the patient that medication, usually for a few weeks or a month, and we see if the medication is having any adverse effects, and we'll stop the medication right then and there for that purpose. If they don't have adverse effects, then we'll assess for changes in weight and repetitive drives even in a month. We expect something to occur within a month, within a month at least of getting to a therapeutic dose. Sometimes it takes longer than a month to escalate to a therapeutic dose. But if there's any apparent benefit of the drug, even a modest weight loss or a decrease in appetite, we'll then go for three months. And at three months, we really make the major decision. Now, if the patient really loses substantially less than 5% of their weight, then we'll typically stop the drug and start a new anti-obesity medication. If they lose greater than 10% of their weight, of course, that's terrific for most of the drugs that we use, then we would continue that drug, and we'll continue it indefinitely to maintain the benefit of that drug. And if they lose somewhere in between, here I've represented it as 5% to 10%, we'll continue the drug. We might increase the dose if the side effects of the increased dose are tolerated or if there are no side effects. But once we get to a maximum of the dose and you get to a plateau with that drug, what we will typically do is start a new drug. So we continue the drug, start a new drug, or we stop the drug, start a new drug on the left, or we just continue the drug if we think we're being successful with that drug or combination alone. Once we start a new drug, we start the process all over again, and the process is the same. And it seems pretty cumbersome when you look at a slide like this, but it's actually straightforward. It's what we do for hypertension, it's what we do for diabetes, it's what we do for a lot of chronic diseases. We start something, we see how it's doing, and we either add a substitute or stop there. So how do we choose which drug we're going to use in each one of these steps? Well, the most important thing is contraindications and side effect risk. If you've got somebody with a tachyarrhythmia, an adrenergic agent like Phentermine is not the drug for that person. If you've got somebody with cognitive dysfunction, a drug that might enhance that cognitive dysfunction like Topiramate or Zonisamide is not the best choice. So we look at that first because that's the most important. Second, we look at additional benefits. If somebody has diabetes or prediabetes, one of the agents or types of agents that also treats diabetes is particularly helpful. If somebody has depression, but not bipolar disease, then we might preferentially go to a drug like Bupropion, an antidepressant, not bipolar disease because it can induce mania. If somebody has a seizure disorder, Topiramate treats seizure disorders, it treats migraine headaches, whereas Bupropion lowers the seizure threshold. So we look at each one of these issues of contraindications and additional benefits. We, of course, look at patient preference around dosing and route of administration. The cost of the patient is absolutely critical. No patient will stay on a drug that they can't afford to get a hold of. And then finally, last, least important, is we look at average efficacy because average efficacy, as I've already shown you, doesn't predict the efficacy in any given patient. So with all of this information, we choose a drug, and if we have to use a second drug or a substitute drug or an additional drug, we do go through this exact same process, and it's different for every patient. Now, how do we implement that? So we'll start a drug, and we'll first wait for a patient to be stable because if a patient's gaining weight, and they stop gaining weight, we have less confidence that it was the drug that did it. So we'd like the patient to be stable at whatever weight they're at to start, and then we give the drug, and we see an effect. And if the patient's weight is stable, you have the greatest sensitivity of finding an effect if there's an effect there from the drug, as shown in the slide. Once things stabilize for a period of time, then we'll start a second agent because in this case, the patient hasn't lost as much weight as we might have liked to. And so we start that second agent, we add it to the first agent, and in this case, there was no effect. So in a month, there was a complete failure of treatment, and so we would stop the second drug, start the third drug, and in this case, this idealized version of the third drug worked on top of the first drug, and so you end up with the combination of the first drug and the third drug being the regimen of choice for that patient. Now it's important to emphasize that whatever your intervention, that intervention has to continue indefinitely, just as you would continue an anti-diabetes, anti-hypertensive, cholesterol-lowering agent, an agent for inflammatory disease like rheumatoid arthritis or Crohn's disease, you would continue the agent indefinitely. In this case, showing this idealized curve, the effects of lifestyle intervention are additive with the effects of the drug. If you take the drug away, though, you're going to go back to the effects of the lifestyle intervention alone. This notion that therapy for obesity has to be chronic if it's going to be effective for anything other than an acute intervention like getting somebody into the operating room or into an x-ray therapy machine, beyond that, it has to be chronic, and we'll come back to it in a few minutes, but you can see, you will go back, and so if you're thinking about combinations that involve surgery or combinations that involve endoscopic devices, the therapies have to be chronic in order to make a difference. The safe use protocols that we've developed for each of the anti-obesity medications include a standardized approach to using them on and off label, optimizing their efficacy and safety, and they reflect the best clinical practice, and they enable all prescribers to provide effective individualized anti-obesity pharmacotherapy. They soften provider and patient concerns about pharmacological treatment of obesity and the safety of these drugs, which are quite common in our environment. I also want to talk about the fact that we can use these drugs in combination, and this is, I'm going to show you the results of the Gravitas study that was published two years ago using loraglutide in patients with type 2 diabetes after gastric bypass, and there are two important results of this study. One is, of course, directly tested, giving loraglutide after gastric bypass, and you can see here that in these patients who got loraglutide, shown here in red, they lost about 6% of their weight on top of what the surgery had done, whereas those given a placebo had no significant change in their weight. If you look at the numbers of patients who lost at least 5% additional weight after they had completed the weight loss from surgery, you can see here that compared to placebo where there was virtually nobody who lost 5%, you can see that by half a year into it with the medication that about almost 50% of the patients lost another 5% of their total body weight in addition to the surgery. So that observation is straightforward. This is the only randomized controlled study of the combination of surgery plus medication, but I want to also emphasize that the drug used in this study, loraglutide, is a GLP-1 agonist, and it underscores the fact that despite the fact that concentrations of circulating GLP-1 after bariatric surgery go sky high, particularly after eating meals, that's not the mechanism by which surgery works. Those enormously high levels of GLP-1 probably account for much of the improvement in diabetes because that GLP-1 gets to the pancreas. But most of the effects of GLP-1, including these GLP-1 therapeutic agonists, are working in the brain where the native GLP-1 doesn't get in very well. So the fact that this adding GLP-1 to the GLP-1 that's already stimulated by the gastric bypass or any bariatric procedure, it works because it works through a separate mechanism. Now the emergence of truly effective anti-obesity medications is the next step in the story. I just want to show you that using bariatric surgery is sort of the upper limits of what we can achieve, and lifestyle intervention as sort of the standard of what we can achieve at about 5% durable weight loss, as described by Dr. Opovian, what have we done with medications over the years? Well, what you can see here is that for most of the time between 1960 and now, all the way up to about 2010, we've had drugs that are no better on average than lifestyle intervention. There was a little blip with Fen-Phen in the mid-1990s, and now already we're up to a little bit higher than that in the high single digits, 7 to 9, 10%. But later this year, we're hoping that the semaglutide, which has already been approved for the treatment of diabetes, but at higher doses is being evaluated by the FDA for the treatment of obesity, the semaglutide will be approved. And if it is approved, the phase three studies demonstrate an average 17% total body weight loss with this drug, looking at the full spectrum of phase three studies. More recently, in a very exciting but preliminary study, the combination of this new drug, semaglutide, plus an amylin agonist called coagulantide, has shown an average 25% weight loss in the first small randomized controlled study that has been published. And now once you get to 25%, you're starting to get into the range of bariatric surgery. That combination, if it makes it all the way through to approval, would probably take at least until around late 2024 or early 2025, at the earliest before it would be approved. But what it tells you is that the combination of these two mechanisms of action, GLP-1 agonism and amylin agonism, hold great promise. And even if this particular combination doesn't make it all the way, there likely will be others sitting right behind it. So if we think about the treatment gap that we often talk about in gastrointestinal treatment of obesity, we think about lifestyle therapies and medications as being not terribly effective, but generally safe. And we think of surgery as being safe, but not quite as safe. And we think of being fairly invasive. And we need to do something in the middle, that so-called treatment gap. And if you look at the therapies that we've had endoscopically, they have not really filled the treatment gap. But we anticipate with emerging endoscopic therapies, not only for diabetes, but also for obesity itself, will begin to fill the treatment gap. But as I've already shown you, medications, including semaglutide at an average 17% weight loss, and combinations that include an amylin agonist at an average 25% weight loss, have the potential of basically abrogating what used to be thought of as the treatment gap. That's the market in which we will be operating from this point forward, I believe. So the core principles of obesity treatment, then, are one, the goal of effective treatment is to reduce the inappropriately elevated defended fat mass or set point that caused the obesity in the first place. We have to recognize that there's enormous heterogeneity in the causes and manifestations of obesity, which leads to wide patient-to-patient variability, as I showed you, in the response to all anti-obesity therapies. People who respond to one therapy may not respond to another. Even more importantly, people who fail to respond to a number of different therapies may respond to the next one that you try. Everybody has to be tried, because even the best therapies, like semaglutide, have a failure rate. 17% of people with semaglutide lose, on semaglutide, lose less than 5% of their weight. The strategy, therefore, is to match each patient with the treatment or treatments that are most effective and suited to them, both in terms of their other medical conditions, their risk of complications, and the efficacy of each treatment. What this means in practice for anti-obesity medications is we need to use a trial and error approach, as I described. We have to recognize different patients will respond to different medications, but it's also important to note that medications may be effective as part of a combination that don't work alone. The combination can be synergistic. You have to anticipate long-term use of effective regimens. As I showed you, if you stop the medications, the patients are going to regain the lost weight. What that means is these drugs are not really weight loss drugs. They're anti-obesity medications because you will not see continued weight loss with these drugs any more than you'll see a continued drop in blood pressure or a continued decrease in cholesterol or a continued improvement in hemoglobin A1c with maintenance of the same dose of a particular medication for those diseases. These drugs are also not appetite suppressants because when you get to the new target, to the body's new set point as a result of the drug, the suppression of appetite will start to fade because the body no longer is losing weight. It's maintaining the lower weight. The drug is still working, but the patient doesn't feel it. By calling these drugs weight loss drugs or appetite suppressants, we may be sending the wrong message to the patients, and as I've indicated, shown here. To summarize, treatment of obesity with pharmacotherapy has gone from something that is not quite accepted because it's not really been that effective. It's been misused in the past by certain practitioners and certain patients. Even when misused, it's not been terribly great as a long-term therapy. Phentermine alone was approved in 1959 for a maximum of several weeks use, even though in combination with terfirmate, it's been approved for long-term use. But today with the emergence of new drugs that have a biological basis and that have been tested in a more rigorous way, we can see that we're moving into a new era where pharmacotherapy can stand to take its place alongside bariatric surgery, alongside lifestyle-based therapies. We hope that as we hear the rest of the course for the rest of the day, that endoscopic therapies will also take their place as they get better and better. Thank you very much.

obesity

treatment

societal forces

lifestyle modification

medications

bariatric surgery