Hello, my name is Jennifer Clements and I am clinical professor and director of pharmacy education with the University of South Carolina College of Pharmacy. I'm happy to be covering treatment of obesity for primary care from diagnosis to care management with this presentation having a focus on treatment options. I want to start with just a summary of what the treatment options are for weight management. First we always have to be thinking about lifestyle modifications in a SMART way. SMART stands for Specific, Measurable, Obtainable, Realistic, and Timely. This emphasizes that you need to think SMART in terms of each step of lifestyle modifications such as healthy eating, physical activity, and behavioral therapy for each person you encounter in clinical practice. With that, we could add on specific medications that have indications for weight loss, medical device, or consider a referral to bariatric surgery. Of course, each of these options that we add on to our SMART lifestyle modifications will vary depending on the person in front of us, but when adding on we always need to consider efficacy, risk, and the cost of each option. A comprehensive weight loss program consists of three components, healthy eating, physical activity, and behavioral therapy. Through a comprehensive weight loss program with the emphasis being lifestyle modifications, we really can focus on reducing somebody's risk of morbidity, so a lower quality of life, controlling their concomitant risk factors, reducing their risk of weight-related complications, preventing further weight gain, but we really want to set a SMART but yet evidence-based goal for weight loss. The most clinical practice guidelines do recommend a specific body weight, which initially is about 5% over six months, but some guidelines also recommend up to 10%. We're seeing now, though, that guidelines are recommending a larger and more sustained weight loss because the greater the weight loss, then the greater the benefit the individual can gain. Once they do lose weight, it's going to be very important to focus on maintaining their lower body weight. Now in this particular webinar, we're going to focus on pharmacotherapy, so specific agents with an indication for weight loss are really to be used as adjunct therapy with lifestyle modifications because that's how they were studied in the clinical trials, but we know these medications can result in a clinically meaningful weight loss and have high satisfaction when utilized appropriately and safely in clinical practice. Now among all the clinical trials for these medications, the populations really consisted of those with a body mass index equal to or above 27 in the presence of a weight-related complication or comorbid conditions such as hypertension, dyslipidemia, and diabetes to list some, but the other group that these medications were studied in were people that had a higher BMI being equal to or above 30. Now I wanted to focus on some clinical practice guidelines from endocrinology and obesity organization as well as a diabetes organization. From the American Association of Clinical Endocrinology, their guidelines were published in 2016 focusing on the management for people with a body mass index equal to or above 25. In this particular publication, they provided information on staging as well as severity of complications which then determined what would be the appropriate treatment options which you can see here range from lifestyle modifications to medical therapy with pharmacotherapy as well as then considering surgery for certain candidates. In addition, the ACE clinical practice guidelines for obesity really looked at medications through shared decision-making, so really empowering an individual to be part of that conversation and treatment plan. In this publication, medications really should be chosen based on efficacy, cost, drug, and person-specific factors. Now, based on when the publication was added to the literature, the options included Orlistat, lorcasirin, fentyramine plus topiramate as a brand-name product, bupropion plus naltrexone as a brand-name product, and loraglitide. But since the publication, lorcasirin has been removed from the market given concern of a higher or potential higher risk of cancer. Within this publication, it addresses therapeutic inertia, meaning that if an individual does not achieve their weight loss goals, then therapy can be intensified with the goal of gaining greater weight loss. The Obesity Medicine Association publishes guidance every year, so from the most recent publication at the time of this recording, we have that pharmacotherapy is recommended as it's been studied in the clinical trials. So going back when I showed you the indications for pharmacotherapy, again, this is how it was studied in those clinical trials with the main patient populations. They also provide guidance that if there's therapeutic inertia or you're not achieving the goals that you want to see after three months, you could consider another medication or increase the dose if that's possible. Obviously, increasing the dose depends on what dose you're currently on, but also mainly tolerance is an individual tolerating that current dose, allowing you to go up. But if goals are not met, even with pharmacotherapy, then that could be a time to refer to a specialty clinic to see an obesity medicine specialist or even maybe bariatric surgery. Now from the American Diabetes Association, they have many different sections in their standards of care for diabetes, and so from the 2023 publication, there's a specific section that addresses weight loss and obesity, particularly among those with type 2 diabetes. What's recommended in that particular section is that we see the cornerstone or the components of a comprehensive weight loss program to achieve and maintain a 5% or more weight loss. And again, that's for most people that are living with type 2 diabetes and may be overweight or have obesity. But really when the pharmacotherapy comes in, so meaning the medications indicated for obesity or weight loss, again, is to be used as adjunct with these lifestyle modifications. But whenever you consider one, you have to do a risk versus benefit analysis before writing that first prescription or giving that person the option of obesity pharmacotherapy. These particular recommendations have not changed from the recently released 2024 Standards of Care in Diabetes that just came out one week prior to this recording. Here's a summary of the clinical practice guidelines that may help you think about ones that are less stringent versus more stringent. And this is really based on risk versus efficacy with all the options being lifestyle modifications, existing pharmacotherapy, newer pharmacotherapy, and then of course the last option, bariatric surgery. So this is my way of thinking. I didn't go over the Cardiology plus Obesity Society guidelines given they were published in 2013, so they're already quite a bit older, but they tend to be less stringent with the ones that I did go over in this recording being more stringent because they incorporate a lot of the newer evidence and newer medications that have come out. Now we're going to transition into pharmacotherapy, and the first thing I just want to mention is we do have some agents that were used. We don't want, you know, we can't really talk about the history of these, so they're honorable mentions only because they were here and now they're gone for various reasons, and a lot of it has to do with safety. So these older drugs that are no longer used were taken off the market given their safety concerns, and that's always going to be in the back of our mind when prescribing or hearing about newer drugs that come out for weight loss is because of the history or the path that these have taken. So we always need to be careful with the pharmacotherapy that we do prescribe, and we'll go over each one of those here in a little bit. For dietary supplements, we know that people are buying these from pharmacies or getting them online, maybe even across in different countries based on which product they're trying to find, but we know there's limited to no consistent data in using them, and in fact, they can be quite harmful not only because of their adverse events but potentially drug-drug interactions and also leading to the trips to the emergency room, which further drives up the cost to the individual as well as our healthcare system. So now I'm going to jump into pharmacotherapy with this first slide showing you established agents, so ones that have been around for a long period of time. So when we look at Phentermine by itself as monotherapy, it's indicated for short-term use, meaning up to 12 weeks. It is generic, so it's quite inexpensive, and another benefit to it can be that you start a lower dose. You can titrate up, but it's just once a day. The downside is that based on its mechanism of action and also being structurally similar to a stimulant or amphetamine, it has adverse effects on the cardiovascular system. So we really have to be cautious with someone's blood pressure as well as pulse. You can see with weight loss, it can be kind of a jump starter in someone's weight loss journey, maybe even being used before some of these newer drugs kick in or reach their steady state to have true weight loss benefits. Orlistat is a medication that's available over-the-counter as well as prescription but can be used for a longer period of time, so its data can go up to one year. Depending on which product you use over-the-counter or prescription, the cost could vary. Orlistat is a lipase inhibitor, and so when I think about it, it's really a lifestyle modification drug, meaning it's a lipase inhibitor, so it reduces the absorption of fat by 30%. But if that fat cannot be absorbed, then it has to go somewhere, and that leads to the adverse effects from this medication, which then could increase the risk of intolerance and then discontinuation. But when you really think about what the guidelines recommend, at least an initial 5%, at one year it's not quite there. Again, it could be useful for someone that may need to change what they eat, but there is the concern of those adverse effects. Now kind of going in order in which they were approved by the FDA, I'm going to go over Phentyramine plus Topiramate first. I've already gone over that Phentyramine, working on norepinephrine, its mechanism is through the central nervous system and therefore could have an effect on just suppressing appetite. The same is true with Topiramate, even though it is listed and classified as an anticonvulsant. Its true mechanism is not known, but both of these drugs by themselves can lead to weight loss. So it only means that when adding them together, you get more weight loss. Its data goes up from one to two years, so looking at long-term use, and the cost could vary depending on insurance coverage, or if you wanted to split these into two separate pills, you're not really going to be following the brand name dosing for Kusimia, which is that particular name for this product. You wouldn't be following it if you did your own regimen by splitting them into two individual generic pills. But if you use the brand name product, you have to start at a lower dose, encourage morning administration for two weeks, before then kind of increasing to the 7.546 milligram dose for three months. If they don't lose 3%, you stop it, but if they do, you can push it to 11.25-69 milligrams for two more weeks, and then really get that maximum dose, 15-92 milligrams. Now on these slides, when I go over the medications, you'll see the highlighted adverse event. That just means that it was the most common one, or most commonly reported one in the clinical trials. So whenever you have two medications in one pill, it leads to more drug-drug interactions, as well as more contraindications. One thing I wanted to point out is with weight loss. One year, 6.6% with that 7.5 slash dose, versus you get more with the 15 milligram slash 92 milligram dose. So what that means is you could really get kind of right in the middle to that 7.5, and hit the mark that the national or the clinical practice guidelines recommend. However, if the person's tolerating it, and you go to the maximum dose of the 15 slash 92, you'll get even more. You could see more adverse events, but you'll get more weight loss that's a little bit larger. So it really depends. The dosing is very complicated. You have different strengths than even what those individual medications are. So it becomes very complicated and can be difficult to kind of grasp when you've been used to these generic pills for a while. Now I'm going to move on to bupropion plus naltrexone, another one that obviously using two medications, but this really started with bupropion, using it for individuals that were quitting cigarettes and smoking, which means that when they did that, they lost weight. Naltrexone by itself does not promote weight loss. However, it could enhance the effect of bupropion, and therefore the two have been combined to a brand name product called Contrave. Contrave is one that is indicated for long-term use, so one to two years, but the cost again could vary depending on what the person's insurance coverage is. This particular medication is not as complicated with the dosing or the strength that's available. Granted, bupropion 90 is not a common dose you would see when using it for depression or smoking cessation, so that just means it could be a little bit different, but it does have to be titrated. Again, it's not as complicated as the previous medication we went over, but it does have a high pill burden, because when you get to that maximum dose, not only do you have to tell them to take it with meals and make sure it's not a high-fat meal, but you're looking at four pills a day, so two in the morning and two in the evening to be four a day. Nausea was the most common adverse event seen in the clinical trials. Now, because you have bupropion and you also have an opioid antagonist, two pills, two medications and one pill, I mean, leads to more drug-drug interactions and contraindications. If I could spend the entire time talking about this drug, I would love to go into its evidence, because we really could look at how it really didn't hit the mark. When you think of 5%, it didn't even hit that at one year, and some of the statistical analysis, I think, is questionable in its each specific clinical trial leading to FDA approval. So it may be one that, even if you get to maximum dose, you won't see the results you wanted to, which means that you would be stopping the medication. But it is still there as an option and maybe could help jumpstart someone in losing weight. The next one I wanted to go over is loraglutide, which is indicated for long-term use, so one to three years, based on all the clinical evidence that's available. However, because there is no generic with loraglutide, it's a brand name product under Saxenda. It can be expensive. The cost could also, again, vary across the board, depending on insurance. But it is listed as a glucagon-like peptide one receptor agonist, which means as a GLP-1 receptor agonist, it has mechanism on the gut to slow gastric emptying, as well as hit the appetite center in your brain to promote satiety. This particular medication is a subcutaneous, once-daily injection, starting at 0.6 milligrams for a week, and then titrating to the 3 milligrams. The reason it's three is that Saxenda, that's how it was studied for all the clinical trials for obesity. So you want to try to get to three, because that's how individuals in that particular arm were receiving it when they were randomized in the clinical trials. Now, nausea is to be expected based on its mechanism of action, but also with each time you go up in the dose, meaning each titration, would go up, so it's dose-dependent. But with that, it's also transient, meaning once you get to three and you're able to stay on it, the nausea would go away. There also could be various reasons why an individual experiences nausea with a GLP-1 receptor agonist, like loraglitide, or even some of our newer drugs, semaglitide, trizepatide. And it could be a quick education point in terms of asking what they eat, what they drink, in terms of asking what they eat, fatty foods, greasy foods, oily foods, spicy foods, and what they drink could be influencing that nausea more than anything. Based on that gastric emptying, there could be some caution with oral medications. And then there are some contraindications with loraglitide, not as extensive as some of the combination products we saw on the previous slides. But really, some of these relate to animal studies, like with the thyroid cancer, that's really based on some of the early animal studies, like I mentioned, and so not necessarily seen in humans, but something to be aware of. For weight loss versus placebo after one year, about a 5.6% reduction, so slightly over that target. We'll say, though, when using this medication in clinical practice, weight loss tends to be more than what's seen or observed and reported in the clinical trials. So we do have some newer medications on the market. The first one that came out was semaglitide being pushed to a dose of 2.4 milligrams. So this is the brand name of Wagovi that is indicated for long-term use. So data, you know, one to two years. But it can be quite expensive. It is also a GLP-1 receptor agonist, delaying that gastric impending and promoting satiety. The difference between this one and loraglitide is that not only is the strength at which you start and titrate up to, but it's a once weekly subcutaneous injection. So starting out at 0.25 milligrams every week for four weeks, then you're able to titrate monthly to get to that target dose of 2.4 milligrams as it was studied in the step trials. So there's a lot of different step trials that have been published that you can look at. But overall, its weight loss shows the larger and sustained. It's really the first drug that we saw these larger reports coming out, such as the proportion of individuals that lost 15% weight loss from baseline, which is a new outcome in these newer clinical trials with the newer medications. And so it's very exciting to think that we're getting new medications that are pushing or getting closer to bariatric surgery. Another medication to really look out for is trizepatide, 15 milligrams, which would be once a week. So this is the new ZepBound that was approved November 8th of 2023. So it can be used for long term, and it will be expensive as well because it is a brand name product. This is different, though. Trizepatide is a dual incretin, meaning that it is a GLP-1-GIP receptor agonist, so having more effect on those gastrointestinal hormones to delay gastric emptying and promote satiety. You start at a dose of 2.5 milligrams subcutaneously once a week for four weeks, and then titrate up monthly to get to the 15 milligrams, which does have the most benefit for the patient. Which does have the most benefit in terms of weight loss. I would encourage you to really pull the SURMOUT trials as they were studied. Some of these showed very large sustained weight loss effects. So as reported on here, about 21% with the highest dose. And even when you look at participants losing what's recommended in those clinical practice guidelines, we're talking about 85% to 91% of participants. It's a huge number. But some of the most recent evidence is so exciting. So for example, the SURMOUT3 really showed intensive lifestyle modifications for three months. And if they achieved 5% weight loss, then they got randomized to the drug or placebo. Well, most people on average had lost about 6.9% of their body weight after three months with intensive lifestyle. That if they got trizepatide and got to 15, at the end of 78 weeks, they were down about 27%. So this is just a huge, huge breaking news and new product to be using in weight management. However, from the clinical trials, there's always a certain point that you could look at the evidence and look at their weight loss and know, are we on track to be a good responder or a poor responder? And so from these, you can see that if you don't lose a certain percent by a certain period of time, it may be considered that you're a poor responder and therefore you need to be on something different. So I'll take loraglitide as an example. If someone started loraglitide and got to 3 and they were on 3 milligrams for 16 weeks and they lost 3% of their body weight from the time they started the drug, then it means they're a poor responder. We shouldn't be continuing this. We need to be talking about a different option. However, if the same individual, when starting it and getting to 3 and being on it for 16 weeks, actually lost, let's say, 7.5%, they're a good responder. They should continue it. As mentioned in the American Diabetes Standards of Care, you always have to do a risk versus benefit analysis. The way I like to think about it is from the percentage of individuals that lost 5% or 10%, that's really reflective of efficacy. So we could calculate numbers needed to treat versus numbers needed to harm for the most common adverse event. So again, this kind of summarizes numbers needed to treat versus numbers needed to harm the risk of all these different medications that I've covered. However, I would say think about the adverse event because while the GLP-1s or even dual receptor agonists look different with nausea, it's a lower number, we have to think of the nature of that adverse event because it's really when you go up or titrate the dose and usually when you stay on it, it goes away. So I would say think about the adverse event usually when you stay on it, it goes away. There also could be some lifestyle modifications that can be encouraged to further reduce nausea with that particular medication. To be complete, there's other medications you can consider depending on what other comorbid conditions the individual has. So we know metformin could cause a little bit of weight loss really because of the diarrhea that happens. Bupropion by itself, topiramate by itself and so on. Even some have been used in combination. So for example, metformin plus topiramate does have evidence for those that take an atypical antipsychotic and may have gained weight from it. So you could also think not just monotherapy but combination therapy because each of these have different mechanisms of action. So we're getting like a synergistic approach in terms of weight loss kind of off label but because they have another comorbid condition. You may be asking yourself though, what about pharmacotherapy? I mean, we don't see a lot of people on these drugs or now we're just seeing people wanting to be on these drugs. So what's the deal? Well, some of it has to do with the underutilization. Maybe why we don't see them as much or now it's just now growing. We didn't see them in the past is because of the safety concerns or the fact we have to do some monitoring with them. Not just efficacy with their weight and the percentage or waist circumference but monitoring from labs. There's some other regulatory reasons such as fentyramine plus topiramate being under the REMS program given topiramate's effect on pregnancy and the need to get pregnancy tests for those of childbearing age. But the biggest reason I think that we don't use these drugs enough in clinical practice is because of the cost or the co-pays associated with them. So we have to find a way to lower that cost for the individual, especially those that are going to benefit them as well. There's some newer evidence with the newer medications coming out and have already been published and maybe that will further drive down the cost. So an example is semaglutide now has evidence as would go be 2.4 milligrams in lowering cardiovascular events by 20%. So always encouraging you to go to these individual trials since we didn't really dive down deep into each one of those and kind of review all the evidence that's available. So some current and future trends is that because these medications are becoming very popular, we could see some drug shortages and have already. That's also led to some compounded products being done, maybe even where you live and people are paying for those because they want to lose weight. And so they're willing to take something that was not studied in the clinical trials and two, you don't know how it was compounded. So we have to think about those but ultimately we all have to work together as well. We put the person in the middle and we have all the teams or all the specialists and other healthcare professionals from other professions part of this. So we're all able to help that individual achieve their goals and the goals that we target and set because they're going to be specific, measurable, obtainable, realistic and timely. So in conclusion, I just want to add that weight loss is hard but maintenance is harder. So one of the biggest questions will be once someone does achieve their goal, what do you do? And we may not have evidence from that. We may have to rely on real world evidence but we have to look at treating lifelong and even maybe just backing down to the next lowest dose rather than stopping altogether, especially if someone's been successful. Regardless of where they are in their weight loss journey, we need to think personalized, individualized care as well as a smart plan. And that needs to be discussed with lifestyle modifications at every visit. But hopefully at the end of this presentation, you realize that pharmacotherapy is adjunct therapy with lifestyle modifications and the newer drugs provide that larger and sustained weight loss effect. But we always need to look at the risk versus benefit for any person in front of us. So thank you very much for listening. I appreciate your time.

obesity treatment

lifestyle modifications

medications

bariatric surgery

clinical practice guidelines

weight loss medications

personalized care