Hello, and welcome to the webinar, Pharmacotherapy for Obesity, presented by the Association for Bariatric Endoscopy. My name is Marty Roth, and I will be your moderator for this program. Before we get started, there are a few housekeeping items. There will be a question and answer session at the close of the presentation. Please note that this learning event is being recorded and will be posted in GILeap, ASGE's learning management platform. You will have ongoing access to the recording in GILeap as part of your registration. Our presenter for this webinar is Dr. Anthony Millard. Dr. Millard is an assistant professor of medicine at the University of Colorado School of Medicine and an assistant medical director of the clinic at the Auschutz Health and Wellness Center. He completed medical school at Northwestern University Feinberg School of Medicine, his residency in internal medicine at Emory University, and fellowship training in obesity medicine and nutrition at Boston University School of Medicine. Dr. Millard joined the faculty at the University of Colorado in 2019. So at this point, Dr. Millard, I will now turn the presentation over to you. All right. Well, thank you for that introduction. My name is Tony Millard, and this talk will be about medications that assist with weight loss. So when I start a visit with a patient, I'm thinking a lot about their medical history and specifically about conditions on this list that can be influenced by weight or can influence weight themselves. In red are a number of conditions that can concurrently be treated by a weight loss medication. And then in blue are a number of conditions that might be exacerbated by a weight loss medication or might play into a side effect. First we want to start by thinking about some ground rules around medication. So first and foremost are the guidelines around BMI. Think about a BMI of greater than 30 as a qualification to use weight loss medications or a BMI of 27 or greater with a condition that also can be related to increase in weight. So diabetes, blood pressure, cholesterol, sleep apnea, fatty liver, among others. Even things like a family history of certain cancers where we're at a higher risk with obesity, things like endometrial cancer, or even an early family history of heart disease sometimes can qualify a patient as well. We want to think about those coindications. Think about other medical conditions like we listed that might inform our choices. And then we want to start to think about insurance coverage and cost. Unfortunately, oftentimes these medications aren't covered by insurance. So cost can be a factor. We want to think about the side effect profile of the medications relative to their medical history and then patient preference. Sometimes patients see an ad for a medication on TV or they have a friend who's been on a medication and had really good success with and that's what they want to try. As we get them started, we want to think about assessing the benefits three to six months. If it's being covered by insurance, we really need to see at least 5% total body weight loss during that first three to six months on the full dose of the medication in order to continue it for insurance purposes. But it is really important to consider extenuating circumstances. The patient had a big stressor in life, a move or a job change or a family illness or something that might have gotten in the way of their ability to exercise or stick to a particular diet. So it's important to think about the whole picture. We also want to think about these medications in terms of obesity being a chronic disease. This is really something that we've come to learn over the last number of years. The comparison often is made to things like high blood pressure. When you start a patient on a medication for blood pressure and their blood pressure gets better, we don't suddenly take the patient off the medication. We leave them on it to help continue to control their blood pressure. So too is true with weight management. These are medications that patients often need to stay on for an extended period of time and in some cases lifelong. Now I will say there are patients, you know, someone who's diagnosed with high blood pressure who may be able to lose weight and start exercising and stop smoking and stop drinking alcohol who may be able to get off a medication. There are instances like that as it relates to weight loss medications. I'd like to tell patients these medications are a tool to assist with behavior change. And so if we can use the medications to make, you know, some really dramatic behavior changes and that's something that really becomes a habit over time, maybe there is an opportunity to reduce the dose or come off a medication or use it on an as-needed basis. But typically we want to encourage patients to think about these like they do their other medications, a chronic medication for a chronic disease. We may need to think about adding multiple medications over time to address multiple appetite pathways. We'll talk about that on the very next slide. We do want to, in general, avoid using these medications in women who are pregnant or who are trying to become pregnant. It's important to remember not every patient wants a medication and that's okay. And in these cases and in many others, sometimes weight loss is just as attainable by stopping a medication that might be causing some weight gain. We'll come to a slide about those in a few minutes as well. This is the slide that I referenced just a moment ago about the complexity of appetite. This is what we understand of the appetite pathways in the brain right now. For example, the fentramine medication that we'll talk about appears to down-regulate the NPY pathway, may help up-regulate the palm seed pathway. It's thought that the Welbutrin-Naltrexone combination medication works in some of the same ways. It's thought that Topiramate, which is a medication we'll talk about, may work in the leptin pathway. And then the GLP-1s are another category of medications we'll talk about. So you can see where maybe using more than one medication might help address more than one of the pathways in the brain that seems to influence appetite. Terms of a list of medications that cause weight gain, steroids are certainly one that we all know a lot about, prednisone, dexamethasone, among others. Mental health medications, the atypical antipsychotics are one of the biggest groups that we see. Olanzapine, clozapine, quetiapine, among them can be very significant causes of weight gain. Then things like lithium among the SSRIs, paroxetine seems to be the one that causes the most weight gain. Certain diabetes medications, which will stand out because there's some newer medications for diabetes that do help with weight loss. The intermediate acting insulins, especially like regular and NPH, as well as the sulfonylureas and the TZDs. Antiepileptics are another group that stand out because topiramate is an antiepileptic that does help with weight loss. But many of the others like gabapentin and pregabalin can cause significant weight gain. The beta blockers, metoprolol is the one that we see most commonly of the group on this list. So a couple are selective beta-1 blockers, a couple are beta-1 and beta-2s. There's no clear common pattern there, but metoprolol is definitely the one that we see most commonly. And then propranolol, which is a medicine that can be used to prevent migraines, so too can topiramate. So sometimes if someone's on propranolol, a switch to topiramate can be a good option. Among contraceptives, this is often a question that we get from patients, do oral contraceptives cause weight gain? Do any of the other do the same? The depo is absolutely the one that seems to cause the most weight gain as well as the implants. And then antiretrovirals, this is something we've come a long way on over the years, but the protease inhibitors can as well. And then antihistamines, things like diphenhydramine, certainly at much higher doses and long-term sort of chronic use, maybe for sleep or another condition. That's another one that we think about too. This is just a couple of different ways to frame these medications, the antihypertensives, the antidepressants, and the anti-diabetes medications, thinking about the ones that cause weight gain, the ones that may be weight neutral, and then ones that may assist with weight loss. This is another great slide from a couple of my colleagues in Colorado. Just again, another way to think about these medications, the classes, and what to be on the lookout for. Now let's turn to thinking about the medications that can help us assist with weight loss. We'll go through the list of each of these here. It is important to recognize that a couple of these are off-label use, can be very effective to help with weight loss, but just important to make patients aware that these are not FDA approved specifically for the purpose of weight loss. We use them for a second condition, and then we'll cover loraglitide and semaglitide later in the section on diabetes. We'll start with fentramine. This really is our workhorse medication in terms of the mechanism. We do think that it stimulates hypothalamic release of norepinephrine, which again, in turn, turns out to act on the NPY and POMC pathways. It's a reasonably cost-effective medication out of pocket, $15 on the lower end, some times it's a little bit higher than that. In most locations, there's at least one retail pharmacy that carries it in the $15 to $20 range. Sometimes it can be covered by insurance, but this varies by insurance company and by state. In terms of dosing, there are four different doses that you can use. It does come in two forms, the hydrochloride salt and the resin. It doesn't seem like there's much of a difference clinically between the two. It's thought that the resin may slow the GI absorption of fentramine. In terms of dosing, we typically start at eight milligrams once a day. And the eight milligram dose gives us the flexibility to either increase dose up to 15 or half of the 37.5 milligram tablet, or increase the frequency, meaning we use it twice a day or maybe even three times a day. Timing is really important with fentramine. It seems to peak in our system at about three to four hours, and then it seems to start to wane around 10 hours. I usually give patients a range of eight to 12. But to give you an example, if someone takes the fentramine when they wake up in the morning at 6 a.m., but their biggest meal is at dinnertime, or maybe there's someone who deals with night eating, they're eating an extra meal or snack at nine or 10 o'clock at night, taking the fentramine at six in the morning may not be enough to help them. They may not get enough appetite suppression in those later hours. So it might be important to have them take the medicine at 10 in the morning, or maybe even take it as late as noon, keeping in mind, though, that it's a stimulant, it's something that can keep patients up. So we don't want it to interfere too late into the day in terms of potentially interfering with sleep. No other co-indications, though, all of the stimulant medications do offer a potential benefit in terms of energy level or in concentration. You have medications like methylphenidate that are more geared toward concentration and may help a little bit with appetite. Fentramines at the other end of the spectrum may be more likely to help with appetite. Maybe you find a little bit of benefit in those other areas. Side effects, you want to think about classic stimulant side effects, increase in heart rate, increase in blood pressure, difficulty sleeping, especially if we take the medicine too late in the day. And then dry mouth is by far the most common one that we see. This can be helpful just in doing a little bit of detective work. Patients may have been on a weight loss medication in the past. They may not remember the name of it, but asking whether it was something that caused dry mouth can kind of give you a sense for whether it was fentramine or one of the other stimulant medications. In terms of contraindications, cardiac disease is a big one, hypertension and arrhythmias are probably the two most common ones that we see. As far as pulmonary hypertension, this was something that was seen with the fen-phen diet pill that was around in the 90s before it was taken off the market because it was seen to cause significant problems with pulmonary hypertension and with heart valves. This was fenfluramine combined with fentramine. It's been since thought that fentramine alone is a safe medication to use, may have a little impact on pulmonary hypertension. So if it's a more moderate or severe case of pH, we might talk with the lung doctors before thinking about using it, but if it's really mild, we might be able to get away with using it. From a renal perspective, the GFR under 15, we just want to steer clear of it. GFR is between 15 and 30. Maybe we can get away with a lower dose of it. And then the remainder of the contraindications are all things that can be exacerbated by upper medications or a stimulant state. So hyperthyroidism, bipolar, concurrent use of stimulants, we try not to use more than one of them at a time. Seizures are another one. And then history of drug abuse, which we'll talk about on the next slide. So fentramine is a scheduled drug. It is a controlled substance. As a Schedule IV, it does seem to have a very low abuse potential. It is worth knowing that on a urine drug screen, you can get a rare positive for amphetamines. This is also true of metformin. It's also true of bupropion. So other medications that we might think about using that can pop up there. Length of use, this is something that there's some misunderstanding about or some antiquated thoughts about. In a state like Ohio, you have to only use the medication for three months at a time, and you have monthly visits with the prescriber. It is thought to be safe that we can use fentramine for at least a year. In research studies, that's been documented. And then certainly clinically, we have patients who are doing well on it without side effects who stay on it for longer than that. In terms of whether the body develops a tolerance to the medication over time, sometimes this happens really quickly and we need to increase the dose sometimes. Folks do really well on it for a much longer period of time. And then as I said, it really is important to consider state prescribing laws. This is really a visual example of fentramine as our workhorse medication. Looking at data from 2009 to 2015 at weight management practices all across the country, it was found that of the more than 6 million medication days, more than three quarters of them were on fentramine. You can see that loraglutide is sort of at the bottom of the list. That medicine was approved during the course of this study, so certainly those numbers are a little bit skewed. And as more of the medications become available, our use of fentramine will probably drop a little bit, but it's been our workhorse for a really long time. It's been studied going back to the 1950s and 60s. This is actually an interesting study I like to reference from 1968 of fentramine. It was a three-arm trial of continuous fentramine at 30 milligrams a day for 36 weeks relative to an alternating day of fentramine in a placebo versus continuous placebo. You can see that both the continuous and the alternating groups did quite well in terms of weight loss, losing more than 25 pounds over the course of 36 weeks, which is a great result. Certainly, this was at a time where our food environment is a little bit different than it is today, but nevertheless, the results do stand, and occasionally we have a patient who likes to use the medication in an alternating day fashion. I thought the most interesting thing from this study is in the red box in the bottom left, and that is they made an observation that is still very, very true today, that with all of these medications, their effectiveness really does vary from patient to patient unrelated to a degree of obesity to age or other dietary habits. More recent times, a study of fentramine, this is a study that I'll come back to a couple times over the course of this talk, but a seven-arm study including placebo comparing two fentramine doses, two topiramate doses, two fentramine and topiramate doses. You can see that fentramine does reasonably well on its own, 6, 7% weight loss over the course of 28 weeks, so a reasonable place to start for sure. Moving on to topiramate, it's important to know this is an off-label use for weight loss alone. As we'll see in a minute, there are a number of co-indications where we might be able to use topiramate and get some weight loss benefit from it as well, but topiramate for weight loss by itself as monotherapy is considered off-label. It's a carbonic anhydrase inhibitor. As far as our understanding of how it works to help with weight loss, we don't really fully understand it. It may be that GABA or glutamate pathways factor in, but it's still something that is yet to be fully understood. Out-of-pocket cost is very reasonable. There is an extended release version that tends to be much more expensive. With these co-indications, we may be more likely to get this medication covered for a patient. In terms of dosing, I typically start at 25 milligrams at night. This will become more apparent why as we talk about side effects, but 25 at night for a week, then 25 milligrams twice a day if they seem to be doing well on it. It is okay to use at night only. It's okay to use with fentramine, as we'll see. Timing is maybe also important, especially as it relates to evening cravings and to sleep. It does seem to peak in the two to four-hour range. And then effect seems to wane around 12 to 14 hours, so people who are taking it consistently twice a day don't seem to see much of an issue here. This is where I think the value of topiramate becomes apparent. There are a number of conditions that have been studied for possible benefit with topiramate. Formal indications are for migraine prophylaxis and for seizures, as well as for IIH. And then there are a number of off-label uses that, in some cases, do pertain to weight loss itself, both binge eating disorder and to mitigate the metabolic sequelae and weight gain that we see from the atypical antipsychotics. Terms of side effects, this, I think, goes back to medical school and training for a lot of us. I was taught during medical school that the nickname for topiramate was dopiramate to sort of communicate that it's a medication that can make some people feel kind of dopey or groggy. So, cognition is a big thing that we worry about. A paresthesia is just a little bit of tingling in the fingers or toes, not a sign of true nerve damage, and usually is something that abates as time goes on. Taste change is actually a feature and not a bug of the medication, I would argue, but it's important to let patients know this ahead of time. In my clinical experience, it seems that soda is one thing that seems to be most likely affected. People say it's like you open a can of soda and then let it sit for a couple of days. The soda tastes really flat, and then sometimes sweet foods, in particular, don't carry the same punch when someone is taking topiramate. Metabolic acidosis, again, something to keep an eye on, thinking of the carbonic anhydrase inhibitors, and then the teratogenic effects are an important thing, which we'll talk about on the next slide, and then it can be a rare cause of secondary angle closure glaucoma, so certainly any patient who started on topiramate who's reporting acute vision changes should absolutely be seen by an eye doctor. Thinking about contraindications for topiramate, these are all relative. Contraceptives are the biggest one that we deal with. It is thought that topiramate can decrease the serum concentration of either estrogen or progesterone. It seems this is most likely when you're above 200 milligrams for a total daily dose of topiramate. And what I counsel patients on, it is something that can cause irregular menstrual bleeding. We're not positive it's enough of a reduction in estrogen and progesterone to increase the risk of pregnancy. But the bottom line for me in clinic is that I always err on the side of caution because of the potential consequence of topiramate. So it's okay to use topiramate alongside an IUD. It is okay to use alongside Depo, but we try to avoid Depo because of the potential for weight gain there. If a woman is on oral contraceptives as a pregnancy measure or on patches, implants, or rings, we do emphasize the need for a second form of contraception. As it relates to kidney stones, topiramate seems to be most likely to increase the risk of calcium-containing stones. The biggest challenge here is most patients don't know what kind of stone that they had. So in general, with a history of kidney stones, we really try to take care to keep the dose under about 100 milligrams a day. The studies that have been done on it do seem to suggest it's a long-term use. We're talking four years or more at higher doses. 300 milligrams or higher is what seems to really increase the risk of stones. But really trying to emphasize do no harm here. We try to keep the dose at 100 milligrams a day or below, and this is a shared decision-making process with patients. If they can tell us very clearly, I had a struvite stone, I had a uric acid stone, then maybe this is something we can use a bit more aggressively. And then certainly jobs that require mental clarity, it's really important for us to counsel patients that this is a medication that can cause some cognitive issues. So it does seem that at the starting dose of 25 milligrams, we seem to do okay in most. Some notes on topiramate. Length of use, it is something that can be used for an indefinite period of time. Tolerance does vary pretty dramatically. If we do have to stop the medication and we're at higher doses, there are some guidances for how to stop it depending on the indication. For weight loss, it's not entirely clear how we need to do this, but I usually just think about 25 to 50 milligrams per week. In an elderly population, we do want to counsel them about the word finding changes, especially because you might get worried in an elderly patient about signs of a stroke. If the word finding happens soon after they start the medication and they have no other neurologic findings at all, it's probably safe to just stop the topiramate, but I always counsel patients, any other concerns that you see that might make you worried about a stroke, or if you just have a question, it's important to err on the side of caution and be seen or let us know about it. And then if you do start monotherapy and it's ineffective, you can always add phentermine, though usually we start phentermine first and then add the topiramate, or we can switch to zanizumide, which we'll talk about briefly a little bit later on. Thinking about some of the data around topiramate, we'll reference that same study that we talked about before. And again, the topiramate 46, and especially the 92 does reasonably well at 28 weeks. We're looking at somewhere in the neighborhood of 9% of total body weight. So someone who's 200 pounds would be closing in on 20 pounds of weight loss during that time. So again, topiramate alone, even though it's off-label for weight loss itself, does seem to be an effective medication for us to think about using. And then if we also think about it, especially with a condition like binge eating disorder, Dr. McElroy is someone who studied binge eating disorder extensively medications to help treat it. So you'll see her name a little bit later on. This was a study done on binge eating disorder. You can see the particulars here, but the results are pretty stunning. That by week five, the median number of binge eating days was down to zero in the folks who were given topiramate. You can start to see a divergence as early as week three. From a BMI perspective, in 16 weeks, patients on average on topiramate lost two units off their BMI, which is really quite substantial. There wasn't a graph for the average weight loss, but it was around 10 pounds, four and a half kilos over 16 weeks relative to less than a half a pound for the placebo. So the results for use alongside binge eating disorder can be really dramatic. And then topiramate also was a medication to mitigate some of the metabolic changes we see with the atypicals. Most of the studies that have been done here are small. This was the biggest of them. This was done in hospitalized patients in Korea, so hard to generalize to an outpatient population. But these were all patients who are on high weight gaining antipsychotics. Again, placebo controlled versus 100 milligram total daily dose or 200 milligram total daily dose. And you can see that the results were pretty solid, especially for the 200 milligrams of topiramate. You can see some pretty robust weight loss at 12 weeks, a pretty solid change in BMI. And then the responder data on the right, topiramate 200 milligrams a day, more than half of the patients lost 5% of their body weight in 12 weeks, which is really impressive. And a decent percentage lost at least 10% of their body weight. So again, thinking about topiramate for these other indications, binge eating, or when someone is on an atypically antipsychotic, this can be really helpful. Phentermine-topiramate combined. We've been over phentermine, we've been over topiramate. The mechanisms, the side effects and other things like that tend to very much overlap. In terms of cost, this is something that is most cost effectively available through a mail order pharmacy that you can find on the website bearing the trade name of this medication. But $99 a month can be a couple hundred a month when gotten through a local retail pharmacy. Again, coverage very much varies by insurance or by state. We do start with 3.75 of phentermine and 23 of topiramate. Do this for two weeks just as a starting point to check for side effects. And then after that, we double the dose to seven and a half and 46. Usually have the patient stay there until we see them next in the six to eight week mark. Most people seem to do pretty well at the seven and a half, 46, which we'll see in the research data. But sometimes we do need to increase the dose from there. And we usually assess that at each visit moving forward, either up to 11, 2, 5 and 69, or all the way up to the max dose of 15 milligrams of phentermine and 92 topiramate. Timing is less of an issue with the combined pill, though if someone is having an effect that they notice around night eating or a side effect around insomnia, for instance, you may encourage them to adjust the timing of the dose. And then in terms of the contraindications, it really combines the two. So kind of be on the lookout for each of those. It does remain a Schedule IV drug because of the presence of phentermine. And again, thinking about the drug screens. We have safety data on phentermine topiramate for two years, which we'll see in just a minute. And then tolerance again is very much variable. The regulations around state prescribing laws seem to pertain to phentermine alone, but it's important to keep an eye on those. The package insert does recommend a monthly pregnancy test for women of reproductive age. Folks who are really, really solid with their contraception, you know, again, being mindful of topiramate. That's something, it tends to be harder to do this in clinic. But again, that's part of the recommendation. And then if we do need to decrease the dose, there are specific instructions, especially when on a couple of the higher doses. Thinking about the data, again, this is the last time we'll reference this particular study, but you can see that phentermine and topiramate together seem to outperform either of the medications on their own. And then we have a number of RCTs on phentermine topiramate. We have the EQUIP trial, the CONQUER trial, and CEQL. We'll talk a little bit about CEQL here because CEQL was an extension of CONQUER. So you'll get some of the data from both. You can see the enrollment criteria. Again, lifestyle measures, lifestyle counseling all across the board. Placebo versus the 7 1⁄2, 46 versus the 15, 92. And you can see pretty robust weight loss here. More than 10%, especially at the max dose and around 10% for the 7 1⁄2 and 46. It really is notable. What stands out most in this graph is that almost all of the weight loss seems to happen in that first year. And then it's about maintaining it over time. So that speaks to sort of the chronic nature of these conditions. But then also, this might beg the question to if we added another medication or for the folks who are on the 7 1⁄2 and 46, if we went up to the 15, 92, would that be a way to kind of break through that plateau that we're seeing and enhance additional weight loss? Sometimes it's about adding another medication. As far as the responder data, you can see just looking at the 15% line, pretty good response there in terms of at the maximum dose, about 32% of patients saw at least 15% total body weight loss. We'll try to keep that number in mind as we talk about the bupropion naltrexone and then the semaglutide as well. Let's move to talk about bupropion naltrexone. So thinking about the mechanisms, we talked in that earlier slide about how this does seem to work on the NPY and POMC pathways similar to fentramine. The combined medication here is also a fairly expensive one when obtained out of pocket. Also through a mail-order pharmacy, though a different one than the fentramine topiramate. This one also obtainable through the trade name website. In terms of dosing up titration, we do follow a particular structure here, eight milligrams and 90 of bupropion going from one tab daily to twice daily, two in the morning, one at night to two twice a day. Timing seems to be less of an issue with the BID dosing, though if we do have side effects, we wanna stop the increase, maybe go down a level from there. There are no co-indications for the combined medication at this point, but we do think about depression as something that can be modulated by bupropion as well as tobacco cessation. And then for naltrexone, it carries off-label indications for opiate use, for alcohol use, and then there's some question about whether low-dose naltrexone might be beneficial for chronic pain, for certain GI or rheumatologic conditions. Side effects are really where the challenge is with bupropion and naltrexone. They are many, and unfortunately, the nausea, constipation, and headaches seem to be the ones that we see the most commonly. Side effects are somewhat of a challenge with this medication. Some patients do beautifully on it, so it is always worth a try, but I try to counsel patients that side effects might be an issue. And then any formulation of bupropion, we need to be careful about the mental health side of things. Bupropion does carry a black box warning for suicidal thinking. This is primarily in young adults under the age of 24 who have MDD, who have major depressive disorder or another psychiatric condition. It does seem to be most prevalent in the first couple of months on the medication, so it's important to make patients aware of that. And then patients above the age of 65 seem to get a little protective benefit around suicidal thinking from bupropion, so another thing to consider there. Several contraindications to think about. Chronic use of opioids is a big one. Use of methadone or buprenorphine, also on the list. Seizures or any condition that might lower the seizure threshold, it's important to keep aware of as it relates to bupropion as well, and then uncontrolled hypertension is another we commonly see. Thinking about other concerns around the medication, bupropion does interact with a couple of the key cardiac medications. It is not a scheduled drug, not a controlled substance. Again, the UDS is an important thing to think about around amphetamines for bupropion. Length of use, also indefinite. Tolerance can be very variable. And then if cost is an issue but we don't have many other options, occasionally we can use kind of a rough estimate of each of the medications combined. Naltrexone only comes in a 50 milligram tablet, so we have to cut it into quarters to start with, and sometimes this can just turn into crumbles and it can be hard to do, but occasionally this is something that we do find success with. Thinking about the data around this medication, the core trials, there's core one, core two, core with behavioral modification, and core for diabetes. We'll talk briefly about core one. This is placebo versus a total daily dose of 16 and 360, 16 of naltrexone and 360 of lobutrin, or a total daily dose of 32 and 360. Data around bupropion naltrexone is not especially robust. This is data from those who completed the trial, so this is not even the primary analysis, and we can see about 8% weight loss at a year at the maximum dose of bupropion naltrexone, and then a little bit less with just the 16 milligrams total daily dose of naltrexone relative to placebo, and then the responders you can see over on the right. Again, the bottom set of data is those who completed the trial, and those who completed the trial, 10, 15% or more, we're seeing maybe even a step below what we saw in sequel. There is some data for bupropion alone in women with obesity who also have depression, maybe about 4% weight loss, so the naltrexone adds some, but maybe not a lot. There is some data around bupropion naltrexone with the behavior modification plan where we saw about 11% weight loss in a year, but the behavioral modification control arm saw about 7% total body weight loss. So again, some of that number seems to come from behavioral modification, but again, if you can combine those two, bupropion naltrexone with a behavior modification plan, you can still get some really strong, strong results. Let's spend just a minute talking about zonizumide. I mentioned this is kind of a cousin medication to topiramate doesn't seem to have as much influence on GABA activity. The mechanisms for weight loss like topiramate remain a bit unclear. It is generally a relatively cheap medication that we might get some benefit from one of the co-indications listed below. The dosing range can go up as high as 600, it has been studied for that, typically I think about it as 25 to 400. Usually I come to zonizumide in someone who's been on topiramate and either it hasn't been effective or they found side effects and so I'll start at a low dose of 25 per night and then increase weekly from there, 25 milligrams at a time until we get to 100. Then we reassess whether it's worth continuing, worth increasing or just leaving as is. Timing is less of a concern because the half-life is quite long. Thinking about the co-indications, again, the same list as topiramate though even more of these are off-label like migraine prophylaxis, zonizumide really only indicated for seizures but again, something that we can think about using if topiramate isn't an option for one reason or another. Side effects are relatively similar though it does seem that for paresthesias and metabolic acidosis, each of these are a bit less with zonizumide than they are with topiramate. It's really important to emphasize though that the side effect profile differs from patient to patient. We have some who do beautifully on topiramate who might not tolerate zonizumide. More commonly, it's the other way around. Someone who doesn't tolerate topiramate or doesn't find any benefit from it who starts on zonizumide and does quite well with it. So important to think about just the differences from patient to patient. Contraindications are all very similar to topiramate. And then this profile also very similar with one exception and that is zonizumide is considered a sulfa-containing drug. So any allergy risk around on sulfas is important to know about. Zonizumide is considered a non-antibiotic. So if a patient has kind of a mild allergy or mild reaction to sulfa antibiotics, we might be able to get away with using zonizumide. Again, starting at that low dose and going up from there. But certainly if someone has had a significant allergy response even to a sulfa antibiotic, it's probably worth steering clear of. And then if the zonizumide alone isn't effective, but it's not causing side effects, we can think about adding fentramine or bupropion. There is some data around bupropion and zonizumide that was thought to potentially be another candidate for a combination medication. And then if we've tried topiramate, we've tried zonizumide, we can't tolerate either, we might be able to go back to the extended release topiramate obviously cost dependent. There is data around zonizumide for weight loss. You can see here, this was a placebo controlled trial versus 200 or 400 milligrams of zonizumide. At one year, the 200 didn't do exceptionally well, but 400 seemed to do reasonably well. We're talking about eight kilos of weight loss over the course of a year, not bad. Again, especially if we're running out of options in other places, again, this is something to consider using. Orlistat we'll just mention very briefly. This is a medication that is notable because it's available over the counter. It is thought to have kind of a lower side effect profile overall, but the side effects that it does have can be really rate limiting for a lot of patients. The oily stools, the fecal just discharges one that unfortunately patients don't tolerate exceptionally well. So I don't use this medication much in my practice. It does come up every once in a while. But again, just cost wise can be more challenging. All right, so now let's shift gears to talking about diabetes medications that can also help with weight loss. This has been a big area of excitement and research in recent years. We have the GLP-1 receptor agonist. We have metformin, which in an off-label capacity can be used for weight loss and then the SGLT2 inhibitors. We'll talk first about the GLP-1s, which we have our friend the Gila monster to thank because the GLP-1 hormone was first discovered in the venom of Gila monsters in the 1990s. Research over the next number of years has led to a number of GLP-1 receptor agonists coming to market first for diabetes and then also in more recent years for weight loss. This is a hormone that's found in the small intestine. There are receptors as we'll see on the next slide in many organs of the body. And they've been in use for diabetes for more than 15 years now. Seems to act primarily in two ways to assist with weight loss. One, it acts on the appetite receptors in the brain to help curb appetite. And it does also seem to delay gastric emptying, which in some cases can help us feel more full. In other cases may contribute a little bit to the nausea side effect that we see, but again can be very beneficial for weight loss. And then in terms of blood sugar control, it's important to note that these medications only stimulate insulin release by the pancreas in response to glucose, which makes them much less likely to cause hypoglycemia. Cost does vary pretty dramatically by insurance plan and state. Out-of-pocket cost is very, very high in general. Indications for diabetes and then more recently for weight loss. And then co-indications, there is a lot of ongoing research around GLP-1s to assist with fatty liver, to assist with NASH and hepatic fibrosis. And then also some data around major adverse cardiovascular events or MACE and cardiovascular risk reduction. This is a slide just to capture the benefit of GLP-1 by organ. You can see it works in a number of different ways that all seem to be beneficial for metabolic health and for weight loss. The side effects are mostly GI in nature. Abdominal pain, nausea, constipation, maybe causing some nausea and vomiting and diarrhea. It seems to be most common as we start the medication and then with each dose up titration. The effect does seem to wane with time. So if we're using, you know, the lowest dose for four weeks before we move up, maybe the first week or two someone will report nausea and then it seems to get better. And then as we increase it again, we may see some more nausea that fades with time. Slow and steady dose titration can be the way to go here. Pancreatitis, it's unclear if this is a causal relationship. And then hypoglycemia, as I mentioned on the last slide, certainly if someone is also on insulin or a sulfonylurea, that can be an increased risk. And then around loraglitide, there is some question of whether there's a renal side effect to worry about, but at least as of now, we use the medications kind of regardless of renal status, just as long as we have close monitoring there for any changes in kidney function. Chondroindications, we think about medullary thyroid cancer and multiple endocrine neoplasia, personal or family history. These were chondroindications that mostly came from some of the animal studies that were done on the GLP-1s, but it's something just out of an abundance of caution we're careful about in adults as well. And pancreatitis, if the history is confirmed that they've had pancreatitis in the past, we tend to shy away from it. And then diabetic retinopathy, particularly around dulaglutide and semaglutide, especially if a patient has had a history of proliferative diabetic retinopathy, and especially if the A1C drops fairly rapidly in the early stages of treatment. But the main message here is, you know, any question around ophthalmologic complications, and we're thinking about using a GLP-1, we really just want to have the endocrinologist and have the ophthalmologist potentially weigh in on safety. Thinking about the dosing structure of each, we can see that listed out here. These go from oldest GLP-1 to newest at the bottom. Semaglutide is the one where a lot of the excitement is. It's also worth knowing, so these are injectable medications. Dulaglutide is a weekly. Semaglutide is a weekly. Exenatide comes in both a daily and a weekly. But semaglutide is also available in a PO formulation, so someone who's not interested in an injectable medication at all can get semaglutide that way. Let's talk a little bit about the weight loss data, especially around semaglutide, but first the A1Cs. So we can see some pretty robust A1C reduction in some of the earlier exenatide trials that seem to be matched in some of the most recent semaglutide trials, the Sustained 7 series. This is the data that we've really been waiting on related to semaglutide, which is being used for weight loss at a higher dose. It's one milligram for diabetes, one milligram per week, and then for weight loss, it's a dose of 2.4 milligrams per week. So semaglutide was just approved in early June for use with weight loss, and you can see that the data around it is really, really exciting. The benefit, the curves really break very, very early on in the trial, and you can see that the average amount of weight loss for semaglutide is around 15% of total body weight over the course of 68 weeks. So someone who's 200 pounds might see 30 pounds of weight loss or maybe even more than that. And then the responder data on the right, you can see, take a look at that 15% number. Over 50% of patients in this trial saw at least 15% of total body weight loss. So that really outstrips what we saw in SQL and what we saw in the core data series for bupropion and naltrexone. And then 20% total body weight loss, that's almost approaching a surgical amount of weight loss in nearly a third of the patients who receive this medication. I want to spend just a minute talking about metformin. This is a medicine that has indications for a couple of different diabetes and insulin-related states. The mechanisms around weight loss are a bit uncertain. We'll talk briefly about one potential theory in the next slide. It's a relatively cheap medication. We do tend to use the extended release because of the side effect profile. And again, it can be used for PCOS, for prediabetes, diabetes, gestational diabetes. And then there's also some data which we'll review briefly around the metabolic sequelae of the atypical antipsychotics. So side effect profile, the GI community I know is well aware of these, seem to be better off using the extended release compared to the regular release. Lactic acidosis, sort of classically what we learned in medical school. It's worth noting there is some concern around using metformin with topiramate. So again, something to watch out for there. Kidney function is one of the real keys in thinking about contraindications for metformin, especially with a GFR under 30. We want to steer clear of it. If it's 30 to 45 and they're already on metformin, it might be okay to continue at a lower dose. And then with higher GFRs, just monitor very carefully. Other concerns it's important to think about after bariatric surgery, we tend not to want to use the extended release after bariatric surgery because of the difficulty with absorption, specifically in the bypass and rapid gastric emptying with the sleeve. There was a limited recall on the extended release due to manufacturing issues in 2020. We seem to have moved past that. Then it is thought to be safe to use in pregnancy. And there is ongoing work with metformin around aging and cancer prevention. Just briefly in terms of appetite regulation, I will say I do see a handful of patients who are on metformin who feel very strongly that it's something that does modulate appetite. And we haven't really known why that is until relatively recently. It does seem that there is a substance, GDF-15, that does get increased in the hindbrain, which seems to help regulate appetite in some people. It's important to notice the green highlighting that there are people who do see increases in GDF-15 who do not see weight loss. So definitely a fertile area of research and something to keep in mind. But if a patient tells you they're on metformin and they feel like they're seeing an appetite reduction, there may actually be a physiologic reason why. Looking briefly at a little bit of the data around the atypicals, you can see that there is some benefit. This study, over 12 weeks, we saw almost a two-unit reduction in BMI with lifestyle change plus metformin relative to an increase in BMI with placebo. Some additional data here, again, in patients with chronic schizophrenia or schizoaffective disorder, most of them were on a high weight gain antipsychotic, and you can see some additional weight loss benefit around metformin. So potentially thinking about using topiramate and metformin together over time may be able to get some pretty robust data. And then very briefly, just to mention the SGLT2s. These are meds I tend to think are more commonly used in primary care by endocrinologists, by someone like me. I'm not sure that the GI community would need to use them quite as much, but it's important to be aware of them and their effect on weight. These are medications that usually modulate diabetes control through the renal system, reducing reabsorption of filtered glucose, which means you don't see as much of it in the blood, and that may help modulate insulin levels as well, which may have an impact on weight. Cost does vary, again, by plan and by state. There are important side effects to watch out for. There's some question around lower limb amputation in folks with peripheral vascular disease. And then in terms of coindications, this has been a really fertile area of research in recent years, especially around atherosclerosis for the SGLT2s. There is some really good data around the SGLT2s and improving outcomes with congestive heart failure. So just important to be familiar with these and really try to make sure that patients who do have diabetes or do have heart failure are on the medications that are most indicated to assist with weight loss. That just about wraps it up. A quick reminder that this is a really complex area, both of research and clinically. It's important to think about the complexity of appetite, the number of different pathways that might contribute, and thinking about using the medications both in a layered fashion and in a chronic fashion to try to both help our patients lose weight and keep it off in the long run. And we'll be happy to take any questions. Thanks so much. Well, Dr. Millar, thank you very much for that very insightful and informative presentation. We have had several questions come in during the presentation. So I just wanted to remind everyone that if you do need to submit questions, you can do so through the GoToWebinar question box on the right-hand side of your screen. So, Dr. Millard, I will kick this off with the first question. And I'm also going to have a disclaimer that if I mispronounce any of the medications, I'll do my best. But do you find weight gain with lower doses of amitriptyline for functional GI disorders? And then in parentheses, they have 25 to 100 milligrams. Yeah, so the data around amitriptyline does seem to indicate fairly mild weight gain. We're talking, you know, two to four pounds. I'm not really aware of the specific indication for it. I just know that in terms of awareness around a specific indication that might lead to weight gain, but it is one that we do kind of keep an eye on. You know, with all of these medications, it's just really important to note that everybody responds to them differently. I have patients who are on amitriptyline, you know, for sleep, for instance, who are doing beautifully well in terms of weight loss, doesn't seem to really be interfering at all. And others, I had one patient just recently started for migraines, who really without changing her eating pattern, exercise pattern, gained about 10 pounds in the span of a month. So the impact is very different from person to person. And I think it's just important to be aware of any of the medications that have some weight gain data associated with them. And just be mindful of that when thinking about, you know, adjusting medications to sort of best optimize weight loss. Okay, and how about any issues with Phentermine showing up as a positive on a UDS? Yeah, so Phentermine can show up in fairly rare circumstances as an amphetamine positive test. You know, it's something that I actually have not encountered clinically. I have not had a patient where that's happened, but it can just be important to be aware of it. I don't know that it's a reason not to use the medication. Certainly, if you make patients aware of it ahead of time, it's hopefully something that we can get out in front of. And then, you know, it's really interesting just sort of chemically that Metformin and Bupropion are also drugs that we might consider using to assist with weight loss that can also do the same thing. So I think it's more just something to be aware of to try to be out in front of rather than a reason to not use the medication. Okay, all right. Thank you. The next question is, is there any cardiac risk backslash arrhythmias with Phentermine and HIIT exercise regimes? You know, I'm not aware of that particular combination of risk. We definitely have, you know, a lot of people we're trying to get to exercise more who are using medication. I will say, especially at the lower doses of Phentermine, I think the impact in terms of blood pressure and heart rate is generally relatively minimal. We do encourage people to, you know, keep an eye on their blood pressure, keep an eye on heart rate just in case that, you know, for whatever reason, they seem to be someone who responds more acutely to a low dose. You know, in terms of cardiovascular data, there is a decent amount of data that it is safe to use as long as you don't have any of the contraindications to begin with that, you know, a slight increase in heart rate shouldn't be, shouldn't be super problematic. But in terms of the combination of a stimulation of heart rate from exercise and from Phentermine together, you know, just be something to keep a close eye on. But I think in general, starting at a low dose of Phentermine and then, you know, if you can, keeping the eight milligram dose where you use it, you know, instead of once a day, you go to twice a day. That may keep us in a better spot than increasing the once daily dose. You do find patients who are started on 37.5 in the community kind of straight away where in some instances I refer to Phentermine as rocket fuel. It can really boost energy levels, boost concentration. It just, it may increase heart rate and blood pressure in ways that are not as desired. Okay, very good. And then what diet regime and exercise regime do you recommend in addition to medication use? And then in parentheses, they have Mediterranean, Keto, low carb, high protein. What are your opinions on that? Yeah, so, you know, we in our clinic are pretty agnostic when it comes to any one particular diet. You know, certainly if people have specific goals, you know, endurance cardio training may need a few more carbs. Someone who's trying to lose weight and add muscle at the same time may need some extra focus on protein. But, you know, this has been a debate for lots and lots of years. We have people doing well on Keto, on Paleo, on vegetarian, on vegan, on intermittent fasting, on time-restricted eating, Mediterranean diet. Really what it comes down to is the diet that a patient is most able to sustain over time that also helps limit how much they take in in terms of calories overall. That's probably the best we can say in terms of the best diet for somebody right now. Certainly hope that at some point in the future, we can begin to personalize nutrition. You know, it's always fascinating to look at the waterfall plots of big nutrition studies. The one that comes to mind for me is the data fits trial by Chris Gardner and his group at Stanford. And they compared a low-carb to a low-fat diet with behavioral modification over the course of a year. And the waterfall plots of the low-fat versus low-carb are just about identical. You have people losing 30, 40, 50 pounds on a low-carb diet and others who gain 5 or 10 over the course of the trial. And people on a low-fat diet who do the same, who lose 30, 40, 50 pounds and others who gain 10. So I don't know that we can say at this point that there's one diet that fits for everybody. But certainly the diet that you can stick to, that's so, so, so important. And the diet that helps limit overall what you take in. You can have somebody doing a keto diet where they're eating a lot of plant-based fats, unsaturated fats, you know, 16, 1700 calories a day who do beautifully with weight loss. And then you have folks who are, you know, focused on the bacon, bunless, double cheeseburger who are taking in, you know, 3000 calories a day and really aren't seeing much in the way of weight loss. So it's not a one-size-fits-all approach for everybody. And just whatever's most sustainable and can help you limit your caloric intake overall. That's where we try to meet the patient. Yes, definitely. All right. And we have time for just one more question here. But can you please tell us more about weight regain problem after stopping the use of a GLP-1, I believe, analog medication? Yeah. You know, I don't know that there is a ton of data yet around weight regain with the GLP-1 specifically. The step four trial of the step series for semaglutide did look at keeping one part of the semaglutide group on it versus taking the other group off. And the curves diverge very quickly. The group that was maintained on it lost somewhere in the neighborhood of 15, maybe 17% in that arm. Don't quote me specifically on the number. But the group that was taken off it and then just asked to maintain body weight really only ended up losing, I think, 5% over the course of the year. So there can be some significant weight regain when stopping any of the medications. Phentermine, topiramate, bupropion, naltrexone. This is part of why we think about these medications in terms of chronic use. We do see people who feel very strongly that they are not going to be on the medication long term. They don't want to be on any medications long term. And as I mentioned in the talk, I tell patients all the time, the medications are a tool. Some of them are a really, really good tool. But if they can help sort of create sustainable behavior change over time, maybe we can get off the medications in some limited cases. But for the most part, we have to be thinking about these medications as chronic, long term, just like we do blood pressure medications, diabetes medications, cholesterol medications. You can always give a try to coming off of it. But if we start to see some weight regain, we may need to go back on it. In terms of a mechanism, I think it's still a subject of significant research, whether our body sort of readapts to a state without it, whether there's receptor upregulation or downregulation. I don't know that we know specifically yet, but certainly it's an area that we need to know more about. But I think that the emphasis for now should be really on encouraging patients to think about these medications as chronic, long term meds, just like they would any of the other medications we use for chronic disease. All right, well, very good. Well, again, Dr. Millard, thank you so much for the presentation and for your time this evening. And I also want to thank everyone else for joining us for this presentation on pharmacotherapy for obesity. We hope this information is useful to you and your practice. You will be receiving a survey after this program, and we welcome your feedback. Also, as a reminder, a recording of this webinar will be available in approximately one week on ASGE's GILeap learning platform, and you will have ongoing access to this recording as part of your registration. If you have any questions about GILeap, please contact education at ASGE.org. This concludes our webinar. Have a good evening, everyone.

pharmacotherapy

obesity

weight loss

medications

phentermine

topiramate

bupropion naltrexone

SGLT2 inhibitors

GLP-1 receptor agonists

metformin