Hi, everyone, and welcome to today's hands-on Tips to Improve Diabetes Care webinar. Today, our panel will share their expertise on diet, lifestyle, medicine, and beyond, cardio-kidney metabolic strategies for managing obesity in people with type 2 diabetes. And we're glad you're here. I'm Rosalina McCoy, and I will be moderating today's webinar. To share a little bit about myself, I'm an adult endocrinologist and associate professor of medicine at the University of Maryland School of Medicine in Baltimore. My research, which is supported by the NIH, PCORI, and the American Diabetes Association, leverages real-world data to understand and improve the quality, accessibility, and sustainability of diabetes care at both the individual and population levels. I also have the privilege of co-chairing the ADA Professional Practice Committee, and previously served as chair of the ADA's Diabetes and Primary Care Interest Group. We'll spend the next hour together by following the agenda on the screen. We will be using interactive features during today's session. In the chat box, we will send you important links and information throughout today's session. We also want you to get engaged. We will have two poll questions pop up during the presentations, so please keep an eye out for them. We'll use the Zoom Q&A feature at the end of the presentation for panel questions. If you think of a question as our presenters speak, use the Q&A box on your control panel to type your question. That doesn't disturb it, you wanna get them in. Join us next month, here we go, on March 11th, 2025, for the next installment in the hands-on webinar series. You can scan the QR code or the link in the chat box to register. I'll also shout out the ADA is seeking members who are interested in being involved in the ADA's interest group leadership teams, specifically early career representatives. You can scan the QR code for more information. You can play a key role in shaping the next wave of diabetes leaders. Now, I'd like to introduce the panelists for today's webinar. Click on the references button at the bottom of the toolbar to view their biographies. First, Jamie Alondos is an associate professor at UT Southwestern Medical Center and assistant medical director of the UT Southwestern Clinical Research Unit. A specialist in non-surgical weight management and post-bariatric surgery care, Dr. Alondos holds triple board certifications in internal medicine, endocrinology, and obesity medicine. Originally from Trinidad, he earned his medical degree from the Royal College of Surgeons in Ireland, completed his internal medicine training in Dublin, advanced fellowship training at the Mayo Clinic, and a nutrition metabolic diseases fellowship at UT Southwestern. Joining UT Southwestern in 2013, he focused on medical weight loss therapies, bariatric surgery aftercare, cholesterol disorders, and type 2 diabetes. Dr. Alondos frequently publishes his research and is active in organizations such as Obesity Society and the American Diabetes Association. Dina Grazda is a general internist, diplomat of the American Board of Obesity Medicine, and health services researcher, focused on developing, evaluating, and scaling strategies to improve treatment and outcomes for patients with obesity and weight-related conditions, including prediabetes and type 2 diabetes. Her work is supported by NIDDK. She's the director of research and quality for Michigan Medicine's Weight Navigation Program, a clinical research initiative to improve obesity care delivery in primary care settings. She also developed and now serves as the medical director of the Veteran Affairs Ann Arbor Healthcare Systems Weight Management and Metabolic Health Program. So at this time, I'll let our panelists introduce themselves and state their disclosures. Hi, everyone. Thanks for the kind introduction, Dr. McCoy. Hi, I'm Jamiel Mandoz, and here are my disclosures. And I'm Dina Grazda, and here are my disclosures. We have, I think, one more slide with five. We now turn, hopefully we should have our slides for our first speaker. You want me to share my slides? Yes, please. Perfect. Let's see. Coming slowly because I somehow, let's see. Share, okay. Here we go. And then I think I just need to swap my screens here. So give me a second. Okay. How's that? Perfect. Thank you so much. We're really excited for your talk. All right. Well, thank you all. Thanks for inviting me to speak today. I just want to acknowledge that this is a really big topic that is hard to cover in depth within just a 20-minute timeframe. So what I've tried to do is kind of pull out key ideas, my slides are, I think, well-referenced, and then there are some additional, a Word document of maybe 50 to 60 references that inform this talk that I think can be provided if you want to look into things in more detail. So I want to start by introducing a patient I'll call Ms. M. Now, Ms. M is a 50-year-old woman. She has a history of class three obesity, hypertension, and type two diabetes, which has been well-controlled on Metformin up until this point. However, over the past several years, she's had a rise in her weight, and this has been accompanied by an increase in her hemoglobin A1C, which is now 12.5%. She's truly desperate not to start any new medications, and she voices frustration that her doctor has repeatedly advised her to lose weight through dietary change, but has not provided specific recommendations beyond sort of the standard eat less, exercise more. And unfortunately, her experiences and frustrations are typical of the patients we see every day in our clinical practices. So my intention for today's talk is really to help you identify strategies for providing tailored and effective dietary change recommendations to people with type two diabetes like Ms. M. I'll discuss briefly the pathophysiologic link between obesity and type two diabetes. I'll touch on dietary strategies to support weight loss and glycemic control, and I'll end by highlighting some tips that are hopefully helpful for guiding effective dietary changes during brief office visits. So we know that at the population level, the likelihood of type two diabetes increases with greater BMI. However, BMI alone does not tell us about an individual patient's risk for type two diabetes because it does not account for differences in shape, body composition, or body fat distribution. An individual patient's risk for diabetes really relates to where they store body fat. Individuals with a propensity for visceral fat storage, which is really represented in this upper pathway fat storage around the abdomen, as compared to subcutaneous fat storage with fat storage in the buttock and upper thighs, have a greater likelihood of developing type two diabetes at a lower BMI due to fat storage in ectopic organs like the liver and pancreas. Fat storage is largely mediated by insulin, which is an anabolic hormone promoting lipogenesis and inhibiting lipolysis or fat breakdown. And chronically high insulin levels or hyperinsulinemia is a key feature of type two diabetes. This is in contrast, of course, to type one diabetes, which is really characterized by a state of insulin deficiency. And there's a variety of contributors to hyperinsulinemia, but a key contributor is our modern food environment, which results in overnutrition or chronic caloric excess leading to hyperinsulinemia, hypertrophy of fat cells, so the fat cells enlarge and become dysfunctional. And fat is stored in places where it shouldn't be stored, like the liver, pancreas, and skeletal muscle. This results in insulin resistance due to downregulation of insulin receptors at these sites. Weight loss can reduce ectopic fat and improve glycemic control through enhanced insulin sensitivity. And it really doesn't take a lot of weight loss for patients to have glycemic improvement. As little as three to 5% body weight loss can be beneficial. Greater weight loss, typically in excess of 50 or of 10% body weight loss or 15 kilograms, if we're thinking about absolute weight change, can support even greater glycemic improvements in type two diabetes remission. Type two diabetes remission is increasingly kind of viewed as a feasible, viable target for type two diabetes management. And it's defined as an A1c of less than 6.5% following cessation of glucose lowering therapy. So dietary change is really foundational to any effective weight loss treatment. Of course, dietary interventions can be used as isolated strategies or in combination with medications and surgery. And there are multiple evidence-based dietary strategies. A number of them are listed here on this left-hand column. It's surprisingly difficult to help patients make dietary change or engage in one of these named eating patterns in the context of clinic visits. I think there's a variety of reasons for this. One is we don't have a lot of time. We don't have a lot of training. And I think we've really been let down by nutrition science where there's been a tendency to focus on differences between diets and sort of a hyper fixation on identifying the single best dietary strategy, which one of the take-home messages from this talk is that there is no single best approach and all eating patterns can be highly effective for individual patients. I like this slide, which is from a recent New England Journal article because I think it demonstrates areas of overlap between these named eating patterns. The blue circles represent overlapping components of the diets. Perhaps not surprisingly, the greatest weight loss occurs with the most restrictive diets. A recent umbrella review of 19 meta-analyses of weight loss diets among people with type 2 diabetes demonstrated that weight loss was greatest with very low energy diets, including meal replacement programs. These tend to be medically supervised interventions that use total diet replacement for about 12 weeks. This is followed by gradual reintroduction of solid foods and then a period of close monitoring and follow-up. These programs have the greatest evidence for supporting type 2 diabetes remission with remission rates directly related to the degree of weight loss. So in this particular study, we see that 86% of individuals who achieved at least 15 kilograms of weight loss achieved type 2 diabetes remission. One limitation to using meal replacements is just that they're not widely available in the US, they're not widely covered by insurers, but certainly this is a treatment option that can be offered if available. Other diets on average have similar weight loss effectiveness and generally support weight loss of about 5% on average at 12 months. So these eating patterns could be any of the named diets that we saw represented on the other slide. And what we need to recognize though is that our patients are not averages, that there is significant individual variation in weight change outcomes with all dietary strategies. So these are data from a clinical trial looking at four diets that differed in their content of dietary carbohydrate and dietary fat. The names of the diets are not particularly important, but these are waterfall plots where each vertical bar represents an individual patient and the vertical bars in the downward direction show weight loss, the vertical bars in the positive direction show weight gain. And so we can really visually appreciate that every eating pattern may be much more or much less effective than the average for individual patients. And so really our challenge in clinical practice is to help patients navigate to the eating pattern that works best for them. So how do these findings get distilled into dietary change recommendations? If you look at the ADA standards of care in diabetes, we see recommendations for individualized eating plans with recognition that to date, the data do not support a specific macronutrient pattern. Eating patterns should emphasize key nutrition principles, which include intake of non-starchy vegetables, whole fruits, legumes, lean proteins, whole grains, nuts and seeds, and low-fat dairy. There should be emphasis on minimizing consumption of certain foods like certain sugar sweetened beverages, processed and ultra processed foods. And consideration should be given to reducing overall carbohydrate intake, which has the most evidence for improving glycemia and may be applied to a variety of eating patterns that meet individual needs and preferences. I think there's a misconception that carb restriction is synonymous with high fat, high protein, high animal protein, but the reality is that carb restriction can be applied to a vegan, vegetarian, Mediterranean style diet as well. And there's really a physiologic rationale for carb restriction, which relates back to our initial discussion about hyperinsulinemia. Dietary carb is the most potent stimulator of insulin secretion. So with a reduction in carb intake, we're dropping insulin levels, allowing for lipolysis or fat mobilization of stored fat, reducing body weight, ectopic fat storage and improving insulin resistance. There are different degrees of carbohydrate restriction and these are sort of arbitrary cutoffs, but in general, many US adults, including individuals with type two diabetes are consuming in excess of 200 or 250 grams of carbohydrate per day. Low carbohydrate diets are defined as less than 130 grams of carbohydrate per day and very low carbohydrate ketogenic diets are defined as less than 20 to 50 grams of carbohydrate per day. Restrictive eating patterns, including very low calorie and very low carbohydrate diets can have dramatic and immediate reductions in glycemia. And so it's sort of beyond the scope of today's talk to go into detail on how to manage medications. However, I think it's really important to be aware of the risks and I'm providing here a reference that can guide sort of proactive anticipatory medication changes for patients that might be engaging in these more restrictive eating patterns. One further disclaimer is that very low carb diets should not be used in conjunction with SGLT2 inhibitors to avoid the rare risk of euglycemic DKA. And now I just wanna transition into how we can help patients make meaningful dietary changes during our office visits. So this is complicated because there are so many factors that influence dietary choices. I like this word cloud because it just conveys how complicated this is and really demonstrates the factors that can influence an individual patient's food choices. This sort of seems self-evident, but I think it's worth saying that before giving any dietary change advice, we really need to make sure that our patients first understand that type two diabetes is a diet related condition. And we need to assess patient's desire to make dietary change. I've certainly had a number of patients who have opted to continue glucose lowering medications, low glucose lowering medications, including escalating doses of insulin, because they want to maintain their current eating patterns. That's enjoyable and preference-sensitive to them, and that's a decision we can support. If a patient does desire to make dietary change, it's really important to assess their ability to make change, asking things like, you know, who in your home does the cooking? Who does the shopping? Who do you live with? What are mealtimes like? Asking whether they're eating on the road. What is their job? What are their food sources? Are they stopping for fast food, gas station? And how likely are those food sources to change? Sometimes people don't have control over where they get their food, and we have to make recommendations that align with their environmental constraints. Budget is another thing. You know, how flexible is their food budget? I like to ask patients what they've tried before, if anything, in terms of dietary change, and I want to know what's worked, what hasn't worked, and why, because it's not a valuable use of limited time to make recommendations that have not worked for patients in the past or that are preference-insensitive. It's also hard to make meaningful recommendations without understanding a patient's baseline eating patterns. One, so, you know, I'll highlight in the next few slides ways that we can guide dietary change. I think the first concept is just working with the patient to make a change that is relatively substantial compared to their baseline. So, again, this requires assessing their baseline eating pattern. I often start by asking patients to just walk me through a typical day of eating, starting with the first meal. If a patient is already using food logs, you can review their food logs in the context of the visit. I ask about snacks, beverages, and number of meals per day. And as I'm listening, I'm trying to kind of identify key culprits of hyperinsulinemia in the patient's diet. Often these are calorie-containing beverages, not just soda, but juice and milk as well, or packaged foods like cereal and granola bars. And if patients are consuming these food items in excess, it could be very reasonable to just start by focusing on changing those particular foods to non-calorie-containing beverages or, for example, switching starchy vegetables like potatoes to non-starchy vegetables like leafy greens or above-ground vegetables. Restricting something is necessary. And so there are really three general dietary change approaches to restriction that are inclusive of the discrete-name diets that we looked at before. So calorie restriction refers to eating less in total but without attention to what is being eaten or when it's being eaten. I would say most of our patients have tried a calorie-restricted approach before coming in for weight management advice. Dietary restriction is eating less of something, some particular element within the diet. So this could be eating less of a particular macronutrient like fat or carbohydrate, or maybe a more specific restriction like no meat or no added sugar. And then time restriction is another option, which refers to restricting eating to certain times, again, typically not concerned with what is being eaten during those time frames. Regardless of the type of restriction, we do want to encourage patients to get sufficient protein intake. The recommended dietary allowance for protein is 0.8 grams of protein per kilogram body weight per day. This is really the minimum amount of protein that's needed to maintain nitrogen balance, and it's often considered too low for maintaining muscle mass or preventing sarcopenia during active weight loss. So there are benefits of higher-protein diets during weight loss. We're thinking 1.2 to 1.6 grams per kilogram body weight per day. There's evidence that higher protein can maintain muscle mass during weight loss, though some studies suggest that protein intake alone is insufficient, and it really has the greatest benefit when combined with strength training. Protein can increase satiety, it can increase energy expenditure, and once patients reach a weight loss plateau, protein intake can help to support maintenance of a weight-reduced state. I like this figure on the right because, again, during a time-limited office visit, maybe all you talk about is how to build a plate, and I think this is sort of a pragmatic, stepwise approach. Pick a protein source, then add non-starchy vegetables, filling about half the plate, adding some fat for satiety and flavor, and then if the patient desires or, you know, if it fits within their carb goal, if they're looking at carb-restricted approaches, they can add some complex carbohydrates. Participants don't have to change every meal at once. There's growing evidence that just changing breakfast from low-carb to high-carb, or sorry, I said that in reverse, from high-carb to low-carb can have glycemic benefits, so changing from something like toast or breakfast cereal to eggs or Greek yogurt can be beneficial. These are figures from two isocaloric interventions showing that participants who ate fewer carbs had improved time and range as compared to a higher-carb breakfast, and the lower-carb breakfast also resulted in fewer, or sorry, lower postprandial glucose excursions in the higher-carb breakfast. We also need to evaluate outcomes, ideally within three to six months, to see if the dietary change is the right fit for an individual patient. I often tell patients, you know, we don't know if something's going to work until we try it, but once we try it, we should know pretty quickly if it's the right fit. So I'm just going to walk you through some of the parameters that I tend to think about. One of the most helpful pieces of information, I think, is this idea of achievement of early weight loss. We know that across multiple weight loss treatments, including dietary interventions, early weight loss, which is defined as weight loss achieved within the first 12 weeks of treatment, is an excellent predictor of future weight loss and weight maintenance. In contrast, individuals who do not achieve early weight loss with one approach likely need additional support or a new treatment option. So if your patient is not losing weight within three months of adhering to the diet, and of course, you want to assess adherence, you will not be doing them any favors by telling them to continue on that plan without offering some additional advice, and it could be a new dietary strategy, medication, or even referral to bariatric surgery. Use of continuous glucose monitoring can guide personalized diet and lifestyle change recommendations. True or false? The answer here is true. Patients can use CGM to gain personal insight into how certain foods or lifestyle behaviors, such as exercise and sleep, influence blood sugar levels. I also think CGM can be useful to navigate sort of the idea of healthy foods or the idea that certain things are universally healthy. In this case, this patient is eating salmon and whole grains, which, you know, are encouraged by the guidelines, but they're having a postprandial glycemic excursion, which resolves when the grains are replaced with non-starchy vegetables. A key area of controversy in nutrition science relates to the effect of low-carb diets on lipid levels, and I just want to acknowledge here that, again, there's variation in outcomes. We tend to see favorable changes in triglycerides and HDL cholesterol, and that total cholesterol and LDL cholesterol can increase, decrease, or remain unchanged, and I have some additional slides at the end of this talk that focus on managing LDL elevations in the context of a low-carb diet, but really, you know, we don't know what's going to happen until we try it. The other thing that we kind of forget to talk about is the patient's subjective experience. Are they enjoying the diet? Is it sustainable for them? What are their hunger and cravings like, and how does it fit within their budget? If we don't ask these questions, we might perceive a patient who's losing weight as doing well, but their ability to maintain their weight loss over time could be compromised by one of these factors. And so, in conclusion, I'm just going to circle back to our patient, Ms. M, who was struggling with her weight and her blood sugar control. She really wanted to prioritize reducing medications or avoiding use of medication. She was not interested in anti-obesity medications or bariatric surgery. She was willing to make any dietary change, but recalled that prior caloric restriction resulted in increased hunger. We talked about the option of carb restriction, and she had a family member who was following this eating pattern, and so she thought this could work for her. She used an app to track carbs, and she did quite well with this approach. Over the course of about a year and a half, she lost 23% of her body weight and was able to reduce her A1c by 5.7% without having to increase medications beyond use of metformin. Now, this was a point in time, and she has had ups and downs over the past year, year and a half, and so I think, like all dietary change interventions, they can be hard to maintain, and so we also have to have follow-up plans and help patients engage in strategies to support weight maintenance. These strategies include higher protein intake, regular physical activity, use of self-monitoring tools, monitoring weight and dietary intake, and then we can also consider adjuvant therapy like anti-obesity medications or bariatric surgery. So, in conclusion, even a small amount of weight loss, 5%, can improve glycemic control, and there is no one-size-fits-all approach to dietary change. I think we need to be non-dogmatic in our approach to diet. We can help patients choose a starting point, recognizing that most dietary change interventions are low-risk, and we really need to assess progress within three months and adjust the treatment plan as needed to help patients achieve their goal. And with that, I will turn it over to my colleague, Dr. Mandos. And I'm sharing my screen. All right, I'm hoping everybody can see my screen, and so I'm going to go ahead with that presumption. Please stop me if you can't. So, here we go. All right, so the learning objectives for this talk are to identify the effects of emerging medications for obesity, and I think I've got about 20 minutes to do it, so buckle up. Here we go. I hope I don't lose any credibility by not having a heat map of the U.S. to open and talk about obesity and obesity care. But what I want to highlight is the kind of growing challenge of obesity, particularly severe or class three obesity. That's for people living with a BMI of 40 or greater over the last 20 years. What we've essentially seen is a doubling of prevalence from about 4.7% of the adult population to almost 1 in 10 people now living with a BMI of 40 or greater. So we know that about 40% or more of the adult population on average is living with obesity. And the proportion of people who are living with severe obesity and the complications is also growing to the point that if we look at prevalence of severe obesity on the right hand side of this figure in recent estimates, now it's 1 in every 7 women between the age of 40 to 60 has a BMI of 40 or greater. And this is a key demographic that many of us will see in our clinical practices. And so what we want to do is focus in on what are effective treatments for obesity in this population? Because we know that obesity is going nowhere quickly. These recent estimates for growth in obesity between now and 2050 project that the prevalence of obesity amongst US adults will increase from about 43% to north of 60% by 2030. Estimates also suggest that in pediatric obesity, it will increase from 1 in 5 children to 1 in 3 children will be living with obesity. And this tracks along with prevalence of obesity-related complications such as diabetes, where the prevalence of diabetes is set to increase from about 16% of adults to more than 26% of adults by 2050. So my first question, true or false, excess and dysfunctional adiposity is a primary driver of cardio-kidney metabolic syndrome, the CKM syndrome. And the answer is true. So much of the paradigm in thinking around obesity as a disease and as a driver for health complications that traditionally we've paid attention to, such as things such as hypertension, hyperlipidemia, the metabolic syndrome, type 2 diabetes, things that drive end organ damage in our body has really shifted to the point that we really now are focusing on how do we work upstream to address excess and dysfunctional adiposity, i.e., prevent and treat obesity in order to prevent and treat the complications that we've really focused in on over the last several decades. And this is something that we've done with type 2 diabetes as well. So much of kind of what we've done over the last many decades has been on a glucocentric downstream approach, where many of the things that we were focused in on were glycemic outcomes, where now we're thinking that particularly for type 2 diabetes, what we need to do is address the upstream excess and dysfunctional adiposity that drives a lot of the intermediary complications that leads to the end organ damage and macro and microvascular complications that ultimately we were treating the hyperglycemia to prevent. So there's really been this paradigm shift in treating obesity. But the question is, what does obesity treatment look like or need to look like? When we think of the average person who comes into the office who's looking for care, and I'll give you an idea. The average patient I see in our obesity medicine practice at UT Southwestern has a BMI of about 40 and comes in saying that they would like to decrease their body weight by about 25 to 30 percent of their current weight. And when we kind of explore, well, why is that? Universally almost, the answer is, you know, I want better health. There are things that I'd like to do. And they may have been told by a health care clinician that, hey, you know, in order to be healthy, you need to have a normal or healthy range BMI between 18.5 and 24.9. Or they may have come to that conclusion on their own by staring at a chart, waiting too long for us in the office, right? But really, what we need to do is help to contextualize that comprehensive obesity care is about health outcomes, not just about weight reduction. And so what we need to do is help patients and also our fellow clinicians understand what magnitude of weight change do we need to see in order to help to bring about the health change that you want for them and that they want for themselves? But also, what are the modalities to get there? So when we look at things like improving blood sugar, triglycerides, we can even see changes in that before there's weight reduction with lifestyle modification that is a health behavior that is not a weight loss behavior. When we look at improvements in cardio-kicking metabolic outcomes, typically the literature says somewhere around 5 percent body weight change for people across the spectrum of body weight will lead to improvements in things such as liver steatosis measured on MRI or patient-reported quality of life outcomes. When we look at harder outcomes, such as, for example, changes in NASH activity score for people living with MASH and MASLD, or reductions in apnea hypopnea index for people with sleep apnea, or even remission of type 2 diabetes and reduction in cardiometabolic events, really what we're seeing are reductions in excess of 10 percent body weight or, for disease remission, 15 percent or greater. But what gets us there? When we look at the traditional, if you call it, primary care house wine for obesity, eating less, moving more, lifestyle modification, we typically see somewhere between 3 to 7 percent non-sustained weight reduction with those interventions. To get people to 5 to 10 percent, first-generation or older anti-obesity medications will help people to achieve that. To get over that 15 percent pay line, really second-generation anti-obesity medications are something that can help us to get there. In addition to bariatric surgery, which is still a very effective modality for treating obesity, specifically severe obesity and complications, but due to availability of alternatives, it seems to be falling out of favor. We'll start briefly reviewing FDA-approved anti-obesity medications, starting in the bottom right with oralistat, which is a gastrointestinal lipase inhibitor that inhibits absorption of about a third of dietary fat that's ingested. You can imagine with that that there may be significant gastrointestinal side effects. Next, Phentermine by itself, or in combination with Topiramine, it is an amphetamine-type stimulant that, when combined with Topiramine, which is a GABAergic carbonic anhydrase inhibitor, is one of the more powerful combination of oral anti-obesity medications that is non-incretin-based or non-GLP-1 based. Average weight reduction is about 10% in clinical trials for this combination of people living without type 2 diabetes and can be helpful for treating obesity when GLP-1 or incretin-based agents are not available. Naltrexone bupropion is a combination of what is a dopaminergic norepinephric antidepressant medication combined with a mu opioid receptor antagonist which can be helpful for people across a spectrum of pleasure or reward-driven eating type behaviors that can be very helpful for people to decrease appetite and cravings as part of a weight loss journey. Next, the GLP-1 receptor agonist, liraglutide, was the first to be approved followed by semaglutide. These are GLP-1 receptor agonists that those of us in the diabetes space will be very familiar using for treating hyperglycemia. They work in addition to controlling glycemia when it's elevated, they work centrally in the brain to help to decrease appetite and cravings and also have effects on gastric emptying and accommodation so that people feel full with less food for longer which really kind of shifts away from the traditional restrictive pattern of dieting as kind of we kind of learned about more in the last talk where traditionally the approach towards calorie restriction has been with regards to restricting kind of types of food. There may be kind of time patterns of restriction or a variety of things but I'm not sure about you but I really don't do well with that kind of restrictive approach to anything in life and many of our patients when they think about trying to do something like that indefinitely it can seem like a very kind of overwhelming or daunting task. Trazepatide is the most recently approved anti-obesity medication and it's a dual GIP GLP-1 receptor agonist with some additional effects on GIP which may have additional impacts on things like adipocyte biology as well. When we look at the landscape of body weight change with these agents I just want to kind of orient you here. The green bar that we see across is the typical weight reduction that we see with lifestyle modification and the red bar across the top 20 to 35 percent is a typical weight reduction that we would see with bariatric surgery. What we have towards the left of the figure starting with oralestat through to loraglitide are really what we consider to be the first generation anti-obesity medications with average weight reduction somewhere between five to ten percent and really what we see is that what we have is kind of around lifestyle modification more consistently achieving that but really nothing that would bridge that gap between lifestyle and bariatric surgery. With the advent of semaglutide with average weight reductions around 15 percent and then trazepatide kind of with weight reductions around 21-22 percent we really see kind of a bridging of this gap between lifestyle and bariatric surgery with highly effective pharmacotherapies that appear to do more than just weight reduction and we'll get into that in a second. What I want to talk about though is some of the limitations to how we look at data particularly when patients may see news releases or read about things in the press. Often things are talked about in terms of average weight loss and as Dr. Grazia said our patients are far from average and there's a lot of variability in terms of response. I like to show these data which basically show the proportion of patients achieving a specific magnitude of weight loss for given agents for treating obesity and this is loraglutide, semaglutide 2.4 and trazepatide and what we see is a normal distribution with regards to the magnitude of weight change that's achieved with these agents in addition to and these are people towards the left of these vertical dashed lines. These are people who actually gained weight in the clinical trials so there is a variety of different responses that we see with treatment. When we look at mechanisms of action for these effective agents we briefly talked about GLP-1 receptor agonism kind of working towards kind of glucose homeostasis with increased insulin secretion and glucagon suppression impacts on gastric emptying including central actions on increasing satiety and fullness and decreasing cravings or what many people call food noise to help decrease food intake. The addition of GIP has some additional factors including reductions in gastric acid secretion which some may think may help with tolerability of medications that include GIP receptor agonism but also impacts on lipogenesis and lipolysis that may be helpful. Glucagon is another increase in nutrient stimulated hormone of interest that has been combined in anti-obesity medications and CKM based medications. There are animal data suggesting increased energy expenditure with glucagon agonism and liver specific effects including reductions in lipogenesis and increase in lipolysis that may be helpful for specific complications of excess adiposity such as MASL and MASH. But when we look at the pipeline of things on the way it's more than just the GLP-1 receptor agonism the GLP-GIP we've talked about plus the glucagon there are additional factors such as amylin analogs and PYY and a host of others that are currently under investigation for treating obesity and related complications and so it's a very exciting time to be practicing obesity. But it's also important to acknowledge the paradigm shift that we've had around obesity care that it's a chronic disease and while we have very effective treatments that help to decrease body weight and if we look at these data from the step one extension on the left and surmount with terzapatide on the right what we see is that with treatment of these highly effective agents we have very nice reductions in body weight and with cessation of the treatment and if we follow people out over about a year we see recurrence in body weight of about two-thirds of the weight that they lost with care. Now if this were an antihypertensive study and we were seeing the effect of blood pressure lowering with a antihypertensive agent and then there was this continuation there was rebound hypertension or recurrence of hypertension we wouldn't be surprised yet some because of the way in which obesity is not viewed as a chronic disease will say well this means that the medication does not work. I look at it quite the opposite I say the fact that the weight reduces with treatment says the medication works and the fact that there is recurrence in disease or condition once the medication is discontinued says that the medication was working that the disease is no longer being treated appropriately and there's disease recurrence and so what we need to do is look at how can we support health long term by using evidence-based care to treat obesity given its growing prevalence specifically in the categories of severe obesity. We know that medications are effective for weight maintenance when they're taken chronically. These are data from the semaglutide 2.4 milligram cardiovascular risk reduction select trial following people out over four years and we see a nice sustained reduction in body weight with semaglutide relative to placebo over the four years that people were followed in the select trial and these are weight outcomes and what we have are the three year data from the surmount one trial specifically in this paper by Yastrobov and colleagues looking at people with a history of pre-diabetes and obesity followed out over three years and what we see is a nice sustained reduction in body weight when treated with trizepatide relative to placebo over three year period and then again the off treatment period we see then the beginnings of the recurrence in body weight once the effective therapy is discontinued. When we look at things that are in the pipeline these are non-peer-reviewed data from news releases from the industry company and what this shows is the surmount five clinical trial which is one of the first direct head-to-head comparisons of anti-obesity of obesity medications that are nutrient stimulated based and this is a comparison of trizepatide versus semaglutide 2.4 milligrams and what it shows is that at 72 weeks we see the average weight loss with trizepatide 20.2 percent versus 13.7 with semaglutide 2.4 and so trizepatide provided a 47 percent relative greater weight loss compared to semaglutide and if we look at the categorical weight reduction on the right we see that about 32 percent of people achieve 25 percent or greater weight loss with trizepatide relative to about 16 percent of people who are treated with semaglutide and it can be helpful for us to look at categorical weight loss rather than average weight loss when we're talking with our patients given that health goals or improvements in health are often viewed in terms of magnitude of weight change. You can say well if your goal is to lose 25 percent of your body weight in this study close to a third of people lost that with trizepatide so it can help to contextualize weight changes that can be seen. Here's some other recent news release data this is for cagrisema which is a combination of semaglutide 2.4 milligrams with cagrelentide which is an amylin agonist or an analog that's under investigation and these are results from the redefined one phase three clinical trial for people without a history of type 2 diabetes who are living with obesity who are treated with either cagrisema semaglutide 2.4 or cagrelentide 2.4 versus placebo and what we see is 68 weeks average weight reduction of about 23 percent with cagrisema relative to about 12 percent with cagrelentide alone versus 16 percent with semaglutide alone and 2.3 percent with placebo. So again what we see is kind of a growing body of evidence for the effectiveness of these new and emerging nutrient stimulated hormone type medications for inducing weight loss. But what about different ways of taking it? Most of these have been weekly medications that we've talked about up until this point. What about oral options? These are data from the OASIS-1 phase 3 clinical trial for oral semaglutide which is a glp1 peptide if you recall taken orally and what we see with daily semaglutide 50 milligrams. We see average weight loss of about 17 percent with this relative to about so for about a third of people 37 percent achieving 20 percent weight reduction with this. So it's pretty kind of equivalent to the 2.4 weekly dose but if you kind of think it out 2.4 milligrams injected once a week versus 50 milligrams once a day we can see that it's not very well absorbed. Semaglutide is currently approved for treating diabetes at the 7 and 14 milligram doses and so what we're seeing here is a much higher dose 50 milligrams once a day under investigation for treatment for obesity. Orforglypron is another glp1 receptor agonist under investigation for treating obesity currently in phase 3 clinical trials and these are results from the 36 week phase 2 clinical trial with daily orforglypron which is a glp1 receptor agonist small molecule. So there's less concerns with regards to bioavailability and absorption with this. We see average weight reduction at 36 weeks so much shorter than the phase 3 clinical trials of about 15 percent body weight with close to half of people achieving a 15 percent body weight or greater with this medication. Cervotide is another medication currently under investigation phase 3 clinical trials for treating obesity and it's a combination glp1 receptor agonist and this time a glucagon receptor agonist. We see at 46 weeks here average weight reduction at the highest dose of about 15 percent body weight with close to a third of people achieving 20 percent body weight reduction or greater at just 46 weeks duration. So a very different mechanism action to the others and so we're looking forward to learning how do we differentiate which of these treatments to use. Lastly within this class we're going to touch on retitrutide which is a triple agonist of gip glucagon and glp1 and these are results from the phase 2 clinical trial showing that at 48 weeks we see close about a 24 percent average body weight reduction with almost 70 with about 70 percent of people achieving 20 percent body weight reduction or greater at the highest doses. So again these are phase 2 clinical trial data the phase 3 clinical trials are ongoing there's a lot of development within the space with regards to these nutrient stimulated hormones and the different ways in which they can achieve not just body weight reduction but also also health improvements. When we look at kind of what are current approved kind of indications for obesity medications in the space we've talked about type 2 diabetes there are kind of growing indications including cardiovascular risk reduction including treating obstructive sleep apnea and we know that for our patients with type 2 diabetes there are demonstrated benefits for cardiovascular risk reduction improving renal or kidney health as well as progression to kidney endpoints specifically or particularly for patients with microalbuminuria. To highlight the impacts of people living with type 2 diabetes we have here the trizepatide trials for people living with type 2 diabetes really showing kind of nice weight reductions but also nice hemoglobin a1c reductions and so what we see here is that when we have an average starting hemoglobin a1c of around eight percent after 72 weeks of treatment if we look at targets for a1c for people who are taking the medication 90 or greater achieved an a1c of less than seven and more than half achieved a hemoglobin a1c of less than 5.7 so what we see is really an era of not just effective obesity treatment with regards to weight reduction but also impacting the downstream effects of the obesity on things such as glycemic health. In addition other challenges related to excess adipostere body fat including obstructive sleep apnea so trizepatide was approved by the FDA for treating obstructive sleep apnea in December of last year and what we see here are results from the surmount osa phase three clinical trial showing a nice reduction in body weight of about 18 percent for people treated with trizepatide and a nice reduction apnea hypopnea index and kind of the take-home message for this when we kind of look at criteria for needing CPAP and these were all participants who had moderate to severe obstructive sleep apnea after a year treatment with trizepatide 42 percent of those treated no longer met the criteria of needing CPAP versus 16 placebo so what we have are effective treatments that are helping to address body weight and complications including CPAP and the need to wear c oh sorry obstructive sleep apnea and perhaps the need to wear CPAP so very exciting developments. Also with regards to cardiovascular risk reduction these are the kind of overview results from the select trial that were discussed at ADA two Novembers ago showing that on top of excellent standard of care people without a history of type 2 diabetes with a prior history of atherosclerotic disease such as prior mi or stroke what we see is an additional 20 percent reduction in cardiovascular event cardiovascular mortality non-fatal mi and non-fatal stroke with this treatment what we additionally see are benefits which appear to be irrespective of weight reduction and also irrespective of hemoglobin a1c at baseline I'll quickly kind of go through some MASH data and then hand over to Dr. McCoy for questions just to say that there are significant developments in the MASH and MASL space these are phase three kind of early endpoint data showing resolution of MASH in more than 60 percent of people who were treated with semaglutide who had f2 f3 fibrosis to start with similar data for terzapatide and also for civota tide so what we're seeing is an expanding kind of armamentarium of treatments for cardiometabolic complications of obesity that are addressing excess and dysfunctional adiposity in addition to this visceral adiposity that drives so much of the cardio-kidney metabolic syndrome and with all of these new different agents and you can review these slides later there are a lot of different pathways we can consider about how to choose the best treatment for the patient in the room I'll direct you to a paper that we recently wrote with regards to nutrition considerations for people on these treatments because there's so much in the news about talking about reductions in lean mass with these medications and what we want to do is promote not just weight loss but better health outcomes and particularly if we're prescribing these for older adults with an ASCVD history we want to make sure that we're not worsening functional capacity and increasing the risk of frailty and falls moving forward which really reinforces the role of team-based care to focus in on health for people living with obesity and so I'll kind of wrap that up with making sure that we assess all patients individually for their causes of obesity and other complications have an integrated weight and complication management plan live in a world of ands not ors where we have targeted pharmacotherapy and or bariatric procedures that are part of this integrated plan but also understanding that obesity is a chronic and complex disease and across the life course we may require switching between tracks the same way we would with other chronic diseases of a similar magnitude and what we need to do is make sure that we use medications to support healthy weight and prioritize health not just weight loss and treat obesity as a chronic and complex disease with all of that I'd like to kind of highlight the American Board of Obesity Medicine for those of you interested in gaining additional expertise in obesity please let me know if you have any questions you can contact me offline regarding that and thank you so much for attending today I look forward to answering questions with my colleagues. Thank you so much for this really incredible presentation first before we dive into Q&A remember these five hands-on takeaways from today's panel. Before we start Q&A, I wanted to let you know what to expect after this webinar. Later today, you will receive a post-test by email. Please complete it so you can claim your CE credit. And then look for today's webinar recording on ADA's Institute of Learning page in a few weeks. Please remind any fellow ADA members that they can watch the webinar for one CE credit, eligible until December of 2025. I'd like to thank our panel for their wonderful presentations today. If you haven't done so already, please ask your questions by typing them in the Q&A box. So let me take a look at the many questions that came in, and I'll try to synthesize them because there are so many questions and interests. So first, Dr. Trausta, can you comment on the optimal macronutrient recommendations in terms of both carbohydrate and protein for patients with advanced kidney disease? Yeah, I did see that coming in the chat, and I was texting my nephrology friend because I feel like this is – we always talk about this, that there's really a lot of uncertainty. I mean, I think that the recommendations would say 0.6 to 0.8 grams per kilogram of body weight for patients with stage 4, stage 5 kidney disease. I think whether or not patients need higher protein to prevent sarcopenia with advanced kidney disease I think is an unknown. I think right now there are safety concerns that it could advance kidney disease. There's also some data, although I don't think it's particularly great, to suggest that plant protein as opposed to animal protein may be preferable due to potentially less harm to nephrons that remain. So I would say 0.8, and then, of course, these patients are following with a nephrologist and probably have a renal dietician that can be engaged in providing any more specific recommendations if, for example, somebody is losing a significant degree of weight loss and there's concern about muscle mass loss. Thank you. And the next question is for Dr. Almondos. Would you start a GLP-1 in a patient with obesity, diabetes, and history of GERD and Barrett's esophagus? A history of Barrett's esophagus? Yes, Barrett's. Yeah, you know, and so there's always a concern with something that decreases gastric emptying. You know, are you going to exacerbate underlying gastroesophageal reflux? And I think this is where the integration of nutrition and advice comes in to make sure that we mitigate the risks of kind of exacerbating reflux and its challenges, including Barrett's. And so smaller meals, lower fat, making sure there's appropriate acid suppression. But for all patients with Barrett's, regardless, making sure that there are frank conversations around appropriate screening and follow-up with gastroenterology to make sure that things are detected. For those with a history of Barrett's who are living with severe obesity, there may be indications for doing procedures which may in fact improve their Barrett's esophagus and decrease their risk of this worsening, perhaps including bariatric surgery such as renal gastric bypass, which could be helpful. So I think there are a lot of different options and making sure that patients are aware and are engaged in the process through education about nutrition and regular follow-up. This could be a question for either of our speakers. Will there be a change in BMI reflecting ethnicity differences? I can start. I think, you know, BMI is definitely an imperfect tool and should be used for screening somebody for cardiometabolic and kidney risk. There are data suggesting or showing that certain race, ethnicity groups, particularly South Asians, are at risk for cardiometabolic complications of excess adiposity, much lower BMIs. And so while BMI should kind of guide screening, I think what really it should be is kind of a starting point that could be incorporated into additional factors such as waist-to-hip ratio, height, and other kind of factors where you kind of are looking at other indices. But comprehensive individualized health assessment is needed, particularly in groups who are identified as having greater risk of lower BMI. One question which I think comes up with my patients as well is, you know, the attendee comments that they've never understood how 5% weight loss in a very heavy person who may be 300 pounds or more can make a difference. Can you explain the mechanism to motivate our patients? I mean, I think that this probably goes back to kind of the earlier slides that I showed, which is that, you know, the weight loss is – and actually, the literature to kind of pull this together is quite sparse because I tried to review it in preparation for the talk. My understanding is that when you have fat – like, the process of weight gain is that you have your fat cells increase in number. And, Jamie, feel free to jump in and kind of correct me if I'm saying something that you disagree with, but you have your fat cells increase in number. And then when you cannot increase your fat cells any longer, you have your fat cells enlarge. And so they become hypertrophied. They're large. They're disrupting the surrounding vasculature. They're disrupting the immune system and releasing free fatty acids and cytokines. And so losing 5% body weight at that point shrinks the fat cells enough that that disruption can improve slightly, and you may have mobilization of the stored ectopic fat. But I understand why it's sort of a complicated thing to wrap your head around, around, like, how somebody can have a high BMI and benefit. But I think it really has to do with the fact that the fat cells are shrinking. And so you still have a high number, but they're smaller in size. I don't know, Jamie, if you would add something to that. I think that's a really nice explanation with regards to kind of cardiometabolic improvement with this. I think some of the challenges are beyond cardiometabolic issues. There's also biomechanical and other structural challenges from excess adiposity that may not be reduced by 5% weight reduction alone in someone who has significant adipose stores. And so there may be persistent joint pain or other things with 5% weight loss, depending on what your baseline or starting weight is. So I understand the challenges of how do we contextualize this for our patients? How do we create a narrative and a story that is engaging? And it's not, well, you need to lose 100 pounds. That may seem like a kind of insurmountable task. But engaging with patients, talking through the evidence-based care, I think is a great way to start the conversation, because we're so fortunate to have additional options for obesity care beyond just restrictive dieting. I think that gets at probably our last question that we'll be able to sneak in today. So thank you for staying a little bit over. But do you have recommendations or tips on how to discuss with patients about diet and weight loss without pushing them to the risk of eating disorder? I think this ties into really linking the change to health and really focusing on the fact that we're never targeting a normal BMI. It's the percent weight change that matters. It's the percent weight change that is tied to the health outcome. So trying to help patients understand that we're targeting goals that are not just reflected in the number on the scale. And saying, OK, you're on blood pressure medications. Let's see if we can support 10% weight loss, because that's where we know that people can start having reduction in their antihypertensive medication use. Or focusing on improving health and not just achieving a specific weight. I hope that answers the question. Thank you. Well, even though it pains me not to be able to ask the other great questions that came in, you have to be mindful and respectful of your time. So I want to thank our panel again for sharing their expertise today. And I want to thank each of you for joining us. We hope to see you at another ADA webinar in the future. So this concludes the session. And we hope to see you next month.

diabetes care

type 2 diabetes

diet

lifestyle modifications

obesity complications

weight management

glycemic control

dietary recommendations

continuous glucose monitoring

GLP-1 receptor agonists

patient-centered approach

Obesity Management

Dietary Interventions

Weight Loss

FDA-approved Medications

Semaglutide

Terzapatide

Chronic Disease

Health Outcomes