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Kushner: Hello. I'm Dr Robert Kushner. Welcome to Medscape's InDiscussion series on obesity. Today we'll be discussing obesity pharmacotherapy with our guest, Dr Ania Jastreboff. Dr Jastreboff is an associate professor at the Yale School of Medicine and director, weight management and obesity prevention, medical director of the Yale Stress Center. Welcome, Ania, to InDiscussion.
Jastreboff: Thank you so much for having me, Bob. It's my pleasure.
Kushner: Ania, we're discussing a topic near and dear to your heart. I know, because we've worked together for quite some time. I couldn't think of anyone better to have on as a guest to talk about this topic. We're going to go through a series of questions to explore this topic and help our healthcare providers do a better job understanding and using these medications. I'm going to start off with this broad question: Why would we think about using medications for the treatment of obesity at all?
Jastreboff: That's a great question, Bob. The answer to this is rather simple, but on the other hand, challenging. The reason we use medications to treat obesity is because obesity is a disease. Like any other chronic treatable disease, we need to treat it with interventions that target disease pathophysiology and disease mechanisms. That's exactly what these medications do.
Kushner: Well, let's go a little bit further. Obesity is a disease, for sure, but how do medications work on obesity as a disease to help people lose weight?
Jastreboff: That's a great question. Most of the medications that we use work in the brain. They work on different things — for example, increasing satiety. It's critical because our brain sets how much energy we want to store, and it stores that energy in the form of fat. Our brain decides how much fat we should carry. We don't want to carry too little fat because we don't want to starve. We also don't want to carry too much fat because then we wouldn't be able to do all the things that we do. Our brain decides how much fat to carry, and we call that the defended fat mass set point. Basically, these medications help to reregulate that set point to a healthier place. What's happened on a population level in the setting of this environment, we call the obesogenic environment, filled with all of these highly processed foods, lack of sleep, a lot of stress — all of these different things contribute to an obesogenic environment. On a population level, that defended fat mass set point has been pushed up, which is why so many of us carry extra weight and specifically more fat. These medications help to decrease that defended fat mass set point and help us to carry a healthier amount of fat.
Kushner: From the patient's point of view, Ania, that gets deep for patients. Do they understand it mostly as "my appetite is under better control"? Is that mostly what helped what they would experience when going on medications?
Jastreboff: I think it's really important to speak to our patients and to share the story of obesity as a disease so that they know where we're coming from. In terms of their experience taking these medications, what often occurs is that they do feel full sooner. They do find themselves eating less food. They may find themselves craving different types of food. Instead of craving the foods that they usually wanted, patients may not want them. Overall, it's an experience of not wanting or needing to eat as much and yet feeling quite satisfied with what they're eating, and during that process they lose weight. Again, their brain wants them to carry less fat, they eat less, and other things likely happen in the body in terms of impacting metabolism, and that's being explored. Eventually patients lose weight to a new defended fat mass. They lose the fat mass to a new place.
Kushner: I think you're making it very clear or apparent that these medications really target the underlying disease or pathophysiology of obesity. Not that patients don't need to know that, but I think what they're experiencing is "my appetite is under control." Ania, there are maybe about a half a dozen medications. When you think about hypertension, diabetes, we have tens and tens of medications. With obesity management or pharmacotherapy, it's much more limited. What are what are some of the medications that are available, just to orient the discussion to healthcare providers?
Jastreboff: There are several US Food and Drug Administration (FDA)-approved medications for obesity treatment. We call them anti-obesity medications. There are also medications that providers can use off label to treat patients with obesity. Some of the FDA approved medications include things like naltrexone/bupropion, phentermine/topiramate (you can use phentermine alone), liraglutide, semaglutide, and orlistat. The ones that have been in the news lately and that are being utilized because they're highly effective are medications like semaglutide. Basically, those medications are in a special class. That class we term as nutrient-stimulated hormone-based therapies. What does that mean? "Nutrient stimulated" means they are hormones that are released from our body when we eat. These therapies are based on these hormones, hence, nutrient-stimulated hormone-based therapies. When we eat, our body releases hormones from our intestine or our pancreas. Those hormones inform our brain whether we are hungry, whether we are full, or whether we want to eat a specific type of food. Medications like semaglutide mimic those hormones and inform our brain about those different things.
Kushner: The medications you just mentioned, nutrient-based gut hormones, pancreas and intestine — many of us, you and I, think of this as an inflection point or kind of a game changer. Is that because we're thinking of treating the disease of obesity hormonally and utilizing these natural gut hormones that affect satiety and hunger and so on, and giving and administering back to patients, I guess like insulin for diabetes? Or we're giving it back to individuals to treat the disease? Is that it? Or also the effect and the effectiveness of the drugs?
Jastreboff: I think you're hitting on a lot of really great points. Medications like semaglutide and tirzepatide, which is currently FDA approved for type 2 diabetes but not yet for obesity, those medications have a much higher efficacy. Patients who take these medications lose a significant amount of weight. For example, with semaglutide, the average weight reduction in the STEP 1 trial was 16.9% of total body weight. With tirzepatide in the SURMOUNT-1 trial, the average weight reduction efficacy was 22.5%. In these trials, patients really lost a significant amount of weight. For example, with tirzepatide, nearly 40% of individuals on the highest dose lost a quarter of their body weight. What does that mean in terms of numbers? That means that someone who may have started the study weighing 200 pounds lost down to 150 pounds. These are really impressive results with these nutrient-stimulated hormone-based medications. I do agree that they are transforming obesity treatment. They are transforming the way that we can care for our patients and the impact on health outcomes.
Kushner: Those are impressive numbers. I think people may or may not be familiar with bariatric surgery as kind of that gold standard, most effective one. You're almost approaching that. Not quite. Some of them are actually overlaying what you see in bariatric surgery. Ania, how much more weight loss can one expect from medications, on average, than from lifestyle alone? For example, if you go to a commercial program or you see a registered dietitian, and you kind of deal with the diet and activity all by yourself. How does it compare to that kind of an approach?
Jastreboff: When we use diet and lifestyle, I think we're at a point where we need to reframe and really focus in on health and the health benefits of eating a nutritious diet and healthful foods, and the health benefit of moving more, exercising, physical activity. All of those things are so critical for our health. In terms of efficacy, one of the things that we really focus on is not only weight reduction or losing weight but maintaining that weight reduction. The critical difference is that most people can lose weight; it's the maintaining that's the difficult part. When we think about things like medications, we continue to take them because obesity is a chronic disease. We have to keep on taking the medicine in order to maintain that weight loss, and in order to maintain that weight reduction. That's where the medications are critically different, again, because they're treating that disease pathophysiology.
Kushner: Staying with that theme, let's go into the clinic, if you will, or into the office. You made the case that medications are treating a disease and diet and lifestyle is for health and so on, and they go together, of course. You're saying that it's not one or the other; they're together. But does everyone then need a medication who suffers from obesity, and if not, who does? How do we decide who is a good candidate for medication?
Jastreboff: I think it really does depend on the individual patient; our role is to guide patients, to show them and tell them about the options that they have and then together make that decision. Medications may not be right for everybody. Surgery may not be right for everybody. Various dietary interventions may not be right for every patient. It's really making that decision together with the patient. It's our job to guide them and to help them along their weight journey.
Kushner: We know that the FDA states in the package insert that anyone with a body mass index (BMI) — and we could debate whether that's a good marker or not — of 30 or more, or a BMI at 27 or more with a medical complication, is a candidate for medication. That's the package insert; that's following the rules, if you will. Are there any other signs or symptoms or expressions of the patient where you would think, "you know what, you would really be a good candidate to use a medication"?
Jastreboff: I think about it just like with patients with diabetes, right? If a patient with diabetes comes in and their hemoglobin A1c — their average blood sugar over three months — is elevated, and let's say it's 10 or 11, we would say, "Here are some choices of medications. While you're starting on these medications, I'd also like you to meet with the dietitian. And what do you like to do in terms of physical activity?" I think that's really how we should approach our patients with obesity, to basically guide them in terms of here are some medical or surgical treatments and here are things in terms of maximizing your health as you are treating your obesity and losing weight. I do look at factors you mentioned. For example, if somebody has a BMI of 27, do they also have diabetes? Do they also have high blood pressure? Do they have high cholesterol? And all those things can potentially and hopefully be improved as we treat their obesity. And we know that carrying extra fat and having obesity can lead, if not exacerbate, all these other types of diseases.
Kushner: I like your idea of presenting a continuum of care to patients, like with diabetes, and I push for that entirely. It's kind of like telling a patient, "We've got your back. These are all the treatments we can use. If you don't do well with one, that doesn't mean it's a one-and-done. We have a lot of other options." That's a great way to think about it. Do we have any predictors on how an individual patient will respond to treatment with medication? You said some people average 15% or 16%, yet one third lost more than 20% of their body weight. And are there any indicators of which medication to prescribe if we see a patient in the clinic?
Jastreboff: That's also a great question, and I think one that many of us are investigating now to really try and find that out. Right now, we don't have specific biomarkers. There's no blood test that your doctor can do in order to say that you're going to respond to this medicine or you're not going to respond to this medicine but let's try this one. Hopefully we will have those types of tools available to us relatively soon. Right now, we look at various factors. For example, if you start a patient on a medication and they respond early on, that may be an indicator, but not necessarily. And the reason why I say that is because one of the critical pieces that we haven't yet touched on is that it's really important to start the medications at the lowest dose and go up very slowly in order to both prevent as well as mitigate potential side effects, which most commonly are gastrointestinal. If we start a patient on a low dose, it may mean that they may not necessarily respond to that lowest dose as their body is getting used to it. And then they begin to lose weight as we increase the dose. We do look for that early response, but I think it's critical to give our patients time and go up slowly with these medications to help prevent side effects.
Kushner: I'm so glad you walked right into the prescribing guidance. You're so good at that, and I wonder if you could elaborate just briefly on how to best use some of these newer medications you're talking about, like liraglutide, semaglutide, and tirzepatide, because there is an art, I think, of getting patients over the hump of these side effects. What's your recommendation to a healthcare provider on helping a patient start on these medications and advance them and mitigate those side effects?
Jastreboff: Wonderful question and framing of the conversation. The first thing that I say is, just as we teach our patients about potential side effects before we start other medications, we need to do that with these as well. Basically, saying to the patient that potentially you could have some nausea or some diarrhea or some constipation, or if your nausea is really bad, you could potentially have some vomiting. We'll do everything we can to try to avoid that. The most common side effects are usually nausea, diarrhea, and constipation. The first step is letting our patients know that these can occur. The most important thing the provider can do after teaching the patient and educating them about these side effects is to remember to go up slowly. Always start with the lowest dose, and just because the package insert says that for these once-weekly injectable medications you can go up once a month, you don't have to. In fact, most of the time, I don't do that with my patients. They may need 6 weeks on the lowest dose or the second-to-lowest dose. Going up slowly and really listening to how your patient is doing and checking in with them is important. Additionally, to slow uptitration of the medication, there are certain things our patients can do. I advise them on three things specifically. The first is as they start these medications, to really be mindful and try not to eat past the point of fullness. They'll get full really quickly. Pay attention to that and try not to eat past the point of fullness. The second thing is acknowledging that they may be able to eat more frequently, but smaller amounts. Eating smaller amounts, but more frequently, is also something helpful I recommend. Finally, the third thing is to pay attention to which foods may exacerbate their symptoms or their side effects. If they eat something fatty, maybe it's egg salad, and then they have diarrhea, then if they're keeping a food diary, they may note that during the dose escalation, while the doctor is increasing the dose of the medicine, maybe they'll eat a little bit less of the egg salad and switch it out for something else. Things like fatty foods can often exacerbate their symptoms. For some patients, it's various proteins. For some patients, it's spicy food. So, really tailoring advice and recommendations to the patient. We need to reassure our patients that most of these side effects occur during dose escalation. Once a patient achieves a stable dose, oftentimes, those side effects resolve; if not, they significantly lessen.
Kushner: Great tips, Ania. Thanks so much for walking us through that. We're going to finish up here. I want to take a broader lens, kind of stepping back a little bit. We know that survey data in the US show that about 2% or 3% of patients with obesity are actually prescribed a medication for their disease, obesity. The question is, given how effective you said these medications are and how they treat the underlying disease, why do you think the prescription rates are so low in the United States?
Jastreboff: I think this is changing in real time in front of our eyes. I do think that there have been many barriers and challenges to using these medications overall. Access and affordability remain a huge barrier. Hopefully the work that all of us are doing is going to quickly change that, but we do have to be somewhat patient. I think that these new, very highly effective medications are propelling the field forward. And I think that we're going to see tremendous change in terms of not only the rate of prescribing, but also the optimization of using these amazing clinical tools to help our patients lead healthier lives. So, I think high efficacy is really going to drive this.
Kushner: This has been a really great discussion. What recommendations would you give to a healthcare professional to increase their comfort or competence in starting to use these medications? What can they do?
Jastreboff: There are many different things. One is we do have an American Board of Obesity Medicine, and so they can become board certified. There are several pathways to do that. There's a continuing medical education (CME) pathway, and there's a fellowship pathway. There are over 20 obesity medicine fellowships around the country that clinicians can apply for and complete. There are other educational tools in terms of obesity medicine courses, CMEs, shadowing providers who are providing this kind of care. But really, it's what we do in medical school and then residency. We see this, and we learn how to do it. The difference here is that most of us, when we were in medical school, didn't have this type of education. And that is literally changing before our eyes. When I have a provider who hasn't used these medications before, I usually say, start with one patient, one medicine, and see how it goes. Reach out for advice. I think many, many more physicians and clinicians and providers are gaining the tools they need and the skills they need to take care of patients with obesity. And I think this is going to change and evolve over time. Be confident, know that all of us are here to help. I think the field is going to change and all of us can be part of that change.
Kushner: Thank you. Ania. Those are great tips. And thank you so much for guiding us through this topic of obesity pharmacotherapy. We've had Ania Jastreboff on, discussing obesity pharmacotherapy. I want to thank you so much for joining us. This is Dr Robert Kushner for InDiscussion.
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Cite this: Obesity Rx: How to Use New Medications in Clinic - Medscape - Aug 03, 2023.