Welcome to the American Osteopathic Association applying guideline-directed care for patients with type 2D or type 2 diabetes, with a focus on Leukogon-like peptide 1 receptor agonists. I am Jay Schubert, a professor and a diabetologist in the Department of Clinical Sciences and Community Health at Torrey University, California, College of Osteopathic Medicine. It is my pleasure to introduce my co-presenter, Dr. Kathleen Dungan. Please tell us a little bit about yourself. Thank you, Dr. Schubert. It's great to be here. I am an endocrinologist and a professor of medicine at the Division of Endocrinology and Diabetes and Metabolism at The Ohio State University, and I am very excited to be here. I have a lot of experience with use of GLP-1s, both in the clinical and the research environments. We're so glad you're here. Thank you. This webcast is part of an education component of OMED. As the American Osteopathic Association's premier educational event, OMED is where the brightest minds in the osteopathic medicine profession come together to share knowledge, network, and advance the practice of medicine. Today's program is jointly provided by the AOA and Impact Education, LLC. This activity is supported by an independent educational grant from Nova Nordisk, and we'd like to thank them for their support. Here are our disclosures. I want to call out to everyone just a reminder of the Osteopathic Pledge of Commitment. I also want to call out the AOA Mission and Vision Statements. So here is today's agenda. Dr. Dungy and I will be reviewing key considerations related to the management of type 2 diabetes specific to the utilization of GLP-1 receptor agonists and their glycemic and extraglycemic benefits. Following each of our presentations, we will have a panel discussion surrounding two case scenarios to allow further insight, commentary, and discussion. Let's review the objectives. Our learning objectives for today are to explain how GLP-1 receptor agonists function in treating type 2 diabetes and go over their extraglycemic benefits, examine safety considerations related to GLP-1s, and explore for addressing adverse events associated with their use, and then evaluate the guidance for comprehensive approach to care and early management of type 2 diabetes. Now it's my pleasure to turn over the stage to Dr. Dungy, who will provide us with some important background information related to type 2 diabetes pathophysiology, introduction to the incretin system, and the role of GLP-1 receptor agonists in treatment. I'll turn it over to you. Thank you, Jay. We have learned so much about GLP-1 receptor agonists and the incretin system in the last several decades, and it's really an exciting time to be in practice and be taking care of patients with the availability of these agents. First of all, we are all well aware of the importance of the increasing epidemic of diabetes in the U.S. and also worldwide. In the U.S., over 37 million people have diabetes. A large proportion of them, about 35 million, have type 2 diabetes, with the remaining having type 1 diabetes. And we anticipate that in the coming years, as these trends continue, one in three Americans will develop diabetes during their lifetime. So this is a widely prevalent disease, and it is an increasing public health burden in many respects. And more importantly, we have had a number of advances in care, including a proliferation of medications, increasing technology, both on the provider's side of things and improving access to care and documentation of care with the advent of things like electronic health records, two important policy changes which have improved the access to care for many people, and also to effective implementation of these strategies. And despite all of these advances, glycemic control has, for the most part, stagnated over the years. And we can see here that even in large databases, this is fairly obvious, even if we're looking at a relaxed target of 8% or 9%. And this is a problem that needs to be addressed. We need better treatments, and we need better utilization of these treatments. So why is it that patients aren't able to achieve their therapeutic goals? There are a number of issues going on here. In particular, diabetes is a progressive disease. So that is not widely appreciated and something that we as providers can help our patients understand, that not only are we treating the glucose levels in the here and now, but we also want to be forward thinking and preventing progression of those complications and recognizing that diabetes generally does progress, and also taking into account the seriousness of the condition, particularly in identifying patients with diabetes. And until recently, many of our treatments were pretty limited. Many of them, particularly insulin therapy, increases risk of hypoglycemia and weight gain. And so these are relatively undesirable side effects. And as we'll see moving forward, treatments more and more are not only impacting diabetes, but also the comorbidities specifically. So we've increasingly recognized that type 2 diabetes is a really complex disease in terms of pathophysiology. Some of the high-level pathophysiologic patterns and roles are shown here, but in fact, this even just broadly generalizes the complexity of type 2 diabetes. We used to think of diabetes as really kind of being this triumvirate of impaired insulin secretion and insulin resistance, and that has expanded over the years to include complex mechanisms that involve the brain, that involve the islet cells, and more recently the Incretin effect. So the Incretin system has been known to us as endocrinologists and as physicians for a number of decades. It specifically refers to a system of hormones that are largely produced by the gut that influence how glucose is metabolized specifically when it's administered orally. And we call this the Incretin effect. If you administer the same dose of glucose by mouth, you will get a better insulin response to that glucose than if you administer it intravenously. And it accounts for about 60% or so of the postprandial insulin secretion, so it is definitely not a small effect. And the hormones that are responsible for this are in large part due to GLP-1 and GIP, GIP being glucose-dependent insulinotropic peptide. So as you can see in this diagram, when some form of carbohydrate is taken in by the stomach absorbs it and then it gets absorbed in the small intestine, and at various stages peptides are involved with the metabolism of that glucose. And with the release of GLP-1 in particular, there are effects primarily on promoting secretion of insulin from the beta cells of the pancreas but also inhibitory effects on the alpha cells in terms of secreting glucagon, which in turn promotes suppression of glucose release from the liver. It also has important effects in the appetite centers of the brain to suppress appetite and also inhibits gastric emptying, so with that feedback mechanism in controlling intake as well as managing postprandial glucose. And along the same lines, amylin is also released from the pancreas and also has effects on gastric emptying and suppression of appetite. So the role of incretin hormones, more specifically in glucose homeostasis, is quite complex. They are GLP-1 and other incretins are secreted in response to various components of food intake. In this way they, in particular GLP-1, will stimulate insecretion from the beta cells and it's done in a glucose-dependent manner, meaning that if the glucose level is already low, the insulin secretion will not be stimulated and vice versa. It will be augmented in case of a rising glucose level. And suppression of glucagon is also glucose-dependent. So in other words, by administering these medications, you are not going to exhibit a hypoglycemic response, at least in a clinically relevant manner. Now the gastrointestinal effects of GLP-1 differ when GLP-1 is acting endogenously versus when we administer therapeutic agents. In general, GLP-1 inhibits gastric emptying, but when long-acting GLP-1 receptor agonists are administered long-term, this effect wears off over time. Nevertheless, the effects on gastric emptying increase that feeling of satiety and fullness. This is augmented by the effects in the central nervous system. This is via a complex system of autonomic nerves, particularly the peripheral vagus nerve. Ultimately, this also contributes to a feeling of increasing satiety by influencing several regions of the brain that are involved in appetite and regulation of eating. And here is a graphical demonstration of the incretin effect. We can see on the left-hand panel that following an oral meal or oral glucose challenge in the black line here, there is a strong secretory effect on insulin compared to an intravenous glucose administration, and that's called the incretin effect. In persons with type 2 diabetes, this incretin effect is really diminished, as you can see here on the right. In terms of the effects on type 2 diabetes pathophysiology, we know that there are multiple impacts on insulin secretion, insulin biosynthesis, glucose sensitivity in the beta cells, and effects on the alpha cells in terms of glucagon secretion. We know there's delay in gastric emptying, and at least in some animal models, there is an impact of GLP-1 stimulation on beta cell mass that hasn't quite been established in vivo in humans. And then the effects on weight loss really augment the effects of glucose control, and this is mediated by, to some extent, by delays in gastric emptying and increase in fullness, and decrease in food intake. And then finally, there's this perhaps exciting potential to halt the disease progression, and this is very complex, something that's being evaluated in animal models. We do have some suggestion that GLP-1-based therapies have a greater durability of effect than some other agents, but that is really a very difficult question to tease out, because we aren't sure if these are GLP-1-specific effects, or perhaps effects that might be mediated by weight loss as well. And along those same lines, there are some extra glycemic benefits that have been attributed to GLP-1, and those are summarized here in this slide. Again, how much of this is mediated by GLP-1-specific effects versus glycemic lowering and weight loss benefits can be a challenge to sort out, but nevertheless, we are seeing in a number of different types of studies improvements in cardiovascular and renal outcomes, and in part, they are related to some of these effects, so on the heart and vascular system, we certainly see some cardioprotective effects, reduction in blood pressure, and this is at the expense of a mild increase in heart rate. There are reductions in atherosclerotic lesions. In the kidneys, there is some benefit in terms of the renal sodium handling, and we saw this in some outcome studies, ultimately resulting in improvement in renal outcomes. In the brain, a number of potential neuroprotective effects. There are some inflammatory effects, and this can be observed particularly in adipose and other tissues. There are a number of lipid effects, anticoagulation effects. There are important benefits on the liver, and we're seeing this in metabolic liver disease as well. Now, it's important to recognize that in harnessing GLP-1-based therapies, that a lot of legwork was needed on the laboratory side to accomplish this. GLP-1 really only sticks around in the system for a couple of minutes, and it's degraded actively by DPP-4, which is a pretty ubiquitous enzyme, and so being able to harness GLP-1-based therapies has been an ongoing area of research and has been accomplished in a number of different ways. The incretin-based therapies can be divided into DPP-4 inhibitors listed here, and the GLP-1 receptor agonists. GLP-1 receptor agonists can further be categorized into exendin-based therapies. Exendin is a peptide that was originally discovered or at least characterized from the saliva of the Gila monster. The two therapies that are based upon this peptide, which is resistant to DPP-4 degradation, is loraglitide and lixizenatide. Then the human GLP-1-based analogs include loraglitide, which was the first one to be approved, and it's once daily, and then the once weekly GLP-1 analogs, including duoglutide and semaglutide. Then finally, there has been an increase in the use of and research in agents that have multiple Incretin effects and or dual agonists. And the first of these to be approved was terzapatide, and that is a dual GLP-1 and GIP agonist. And really the goal here is to be recapitulating in a particular therapy, the complex mechanisms of type 2 diabetes pathophysiology. And one other important difference between DPP-4 inhibitors and these GLP-1 based therapies is that GLP-1 receptor agonists really achieve high pharmacologic levels of GLP-1 receptor agonism compared to DPP-4 inhibitors. Now, what are some of these outcomes in terms of end organ effects? And this has been widely studied now for a number of years, and all of these therapies almost have undergone long-term outcomes studies, particularly cardiovascular outcomes trials. And in these studies, three-point MACE, three-point MACE, which includes major adverse cardiovascular events, including myocardial infarction, stroke, and death from heart disease. We see some important benefits with several of these agents, but not with all of them. And for a long time, we've tried to understand whether this is a class effect or not. And there are a lot of differences between some of these clinical trials and some of these therapies that may help explain some of the differences, but we can't rule out drug-specific effects. And so the liraglutide, dulaglutide, and subq-semaglutide all met these endpoints in their cardiovascular outcomes trial and do have the indication for MACE in the label. And dulaglutide and semaglutide in particular showed significant reductions in risk of stroke. And then all of these medications have also demonstrated some benefits with chronic kidney disease. Only one of them, semaglutide, has been studied and results have been reported in a dedicated renal population. And these drugs are also showing some important benefits in metabolic liver disease, in particular, resolution or reversal of steatohepatitis and potentially fibrosis. And then some emerging data suggesting some possible benefit in other neurologic conditions as well. And a number of large meta-analyses have been published. This is one example of a meta-analysis that included seven of the more recent cardiovascular outcomes trials. And we can see here that three-point MACE was reduced significantly across all of these studies, cardiovascular mortality, all-cause mortality, and the renal endpoints. And safety outcomes have also been studied, although there may be some limitations in the ability to study very, very rare safety outcomes. Nevertheless, there wasn't any identified risk of pancreatitis, although that does remain in the label for these medications. There wasn't any signal in terms of pancreatic cancer and no signal in terms of retinopathy. Adverse reactions are a concern for many patients, and it can explain some of the durability and adherence to medications. And so it's really important to acknowledge that not all patients are able to tolerate these medications. Primarily, by far, the most common side effects or adverse reactions are gastrointestinal nature, nausea, vomiting, diarrhea, and constipation. Injection site reactions can vary from drug to drug, but can be a consideration. There are a number of other warnings and contraindications as well. Exenatide and lixizenatide are renally excreted, and in particular, we should be cautious in monitoring renal function in patients who have chronic kidney disease, regardless of the agent that is employed. And in particular, if a patient is experiencing a lot of gastrointestinal side effects and is getting dehydrated, that can cause acute kidney injury. There is the potential for worsening of gastroparesis. So asking patients if they have symptoms potentially of gastroparesis, particularly if they have longstanding diabetes, is helpful. And as I mentioned, acute pancreatitis is an ongoing interest, and pancreatic cancer is really hard to tease out. But certainly, there hasn't been a signal in these large outcomes trials. I should note that in the majority of these outcomes trials, patients with a history of acute pancreatitis were excluded. Now, medullary thyroid cancer is also a contraindication, and MEN2 by extension, because it contains medullary thyroid cancer as one component of the syndrome. And this is because it has been observed in rats. It has not been observed in humans to date, and that's in part because there are very important differences in the physiology and C-cells of rats and humans. And of course, they should not be used during pregnancy. So how can we address these gastrointestinal effects? So first, patients should be aware that they can occur, but most importantly, that they usually go away. So my model is start low and go slow. And many patients are able to overcome these gastrointestinal side effects. They should be advised that having smaller meals and just being mindful to avoid overeating, really trying to avoid high fat foods may be helpful. And other things like moderating alcohol intake should be useful. And in part, some of these can be managed expectantly, and typically, things like antimedics are not necessary, but could be considered. And so again, so starting at the lowest dose, really only escalating as tolerated can really help address these symptoms and prevent their need to interrupt therapy. However, dose de-escalation can also be considered. And this is just another sort of more graphic way of really addressing these, if it's just short-term or mild side effects, you know, just kind of with expectant management, potentially slowing down that dose escalation, and really bringing the patient into the conversation on as to whether these are tolerable or not tolerable, I think can be very helpful. And then differential diagnosis, are there potentially other things that may be contributing to these symptoms? And, you know, then considering potentially adding in those things like anti-nausea or anti-acid therapies. And then considering switching to an alternative GLP-1-based therapy. There are a number of head-to-head studies, and in some cases, some GLP-1-based therapies do have, are associated with lower incidence of nausea. And so, you know, if you have a patient who has a high dose of GLP-1, incidence of nausea, and, you know, how helpful these are, sometimes this is difficult to sort out. But occasionally, if patients had a previous experience with nausea or other gastrointestinal side effects as a limiting problem, this can be addressed. It does not preclude future use. And sometimes revisiting it in the future can be helpful to demonstrate, really, was it the GLP-1-based therapy or maybe something else going on? So I'll summarize here. The incurritant system plays a really important role in glycemic control, particularly with GLP-1 and GIP. And in addition to the glycemic management, there are a number of pleiotropic effects that are observed, including other cardiovascular and renal and liver disease mechanisms. And emerging data, actually, in improving sleep apnea as well. The food regulatory effects have been broadly demonstrated. And the central nervous system effects on the brain appetite centers in particular helps mediate the weight loss. And then finally, the adverse events should be acknowledged. These are primarily gastrointestinal and typically limited. And so proper patient education, awareness, and support can be very helpful in addressing them. And with that, Jay, I will turn it back to you. Thank you so much, Kathleen. I think your presentation sets the stage in terms of the clinical rationale for GLP-1 receptor agonists and best practices for their use. Now, I'm going to talk a bit about a comprehensive approach to type 2 diabetes and discuss where GLP-1s fall in the guidelines and recent literature in the role of treating type 2 diabetes and comorbid conditions. So when we choose to start a treatment with someone, I think there are some key things that we can do for best practices to one, help the patient start off on the right foot, and two, stay engaged in the long run. So first of all, we want to know those unique patient characteristics that are going to make any particular treatment better than other when we're trying to treat their options. And I think letting the patient share their preferences and values allows us to organize a treatment plan that will work for them and fit within their life. That shared decision-making is so important. Once we agree on a plan, we can implement it, but it does require us to continue to be following up and asking our patients to know when they need to let us know that they need help. Once we do that, we really are setting the patient off on the right foot to a plan that they feel like they can endorse and continue it. And I want to highlight you do not have to do this alone. There is so much that has to be involved in when we're helping patients manage their diabetes. So do yourself a favor and make sure that you have send your patients for diabetes self-management education support and medical nutrition therapy. There's good evidence that these interventions work as potently as medications. And we want to make sure our patients have the tools to be able to make decisions for self-management for their diabetes. Certainly we know that we're going to engage in other lifestyle interventions, such as regular physical activity, certainly looking at tobacco cessation. And I think healthy coping with diabetes and healthy problem solving is really important. So assessing our patients where they're at in terms of diabetes distress and other comorbidities is really important because if there are other conditions, particularly mental health conditions, you're going to find that it's really hard for them to do self-management for diabetes. And then as much as we can, certainly I think it's important to highlight there are things in the community and in society that are going to make it harder for us to manage diabetes. And as these things come along, I think it's important to highlight where the things they need to avoid so they can be doing optimal diabetes self-care. Now, this is all about communication. So certainly someone with diabetes is going to be managing this condition every day of their life. This is the gift that doesn't go away. And so it's important for us to communicate with them and make sure we understand what's going to work for them and that we have a shared understanding of the treatment plan and goals so they know whether they're achieving those goals and when they can ask for help. The more that we take time to explain treatment options and more importantly, discuss barriers and how to overcome them, the more likely the patient is going to be successful with that treatment plan and it can improve patient satisfaction and most importantly, clinical outcomes. Now, finally, our patients have a wide range of health literacies and numeracies. Certainly there are cultural backgrounds that may be involved in treatments. And so you will need to meet the patient where they're at because they're the one doing self-management. And again, understanding those factors, whether it's you doing it or doing it as part of a team, is going to allow that patient to understand their treatment and best activate and maintain that treatment. And I want to highlight the tenets of osteopathic medicine. I feel like they fit very well in the management of diabetes. These things go hand in hand. We recognize that the body is a unit. The person is a unit of body, mind and spirit. All those things affect self-management and care and the healthy body is capable of self-regulation, self-healing and health maintenance and we need to remove noxious stimuli such as excessive glucose or sedentary activity or excessive fats so that we can optimize that self-regulation. We certainly know that structure and function are reciprocally interrelated. We know that hyperglycemia can cause shortening of the tendons, which can cause mobility and or other pain-related problems. And we need a functioning musculoskeletal system to activate our body to utilize fuel effectively. And then certainly, any rational treatment is based upon the understanding of these basic principles of body unity, self-regulation and the interrelationship of structure and function. So I think this is a really great place for us to utilize these principles in the management of someone with diabetes. So as we move on to guideline-directed pharmacotherapy, I think it's important for us when we're having that shared decision-making approach with our patients, we should be talking about not only the glycemic benefit of medicines, but the extra glycemic effects of medicines as well. And this is supported by the American Diabetes Association standards of care. We should be looking at things such as the cardiovascular benefits, the renal benefits, certainly the risk of hyperglycemia, the impact on weight, and of course, cost and access and availability of these medicines for our patients. We were going to pay attention to adverse reactions and tolerability and ultimately the patient preferences. And if we have all of those things in, we have plenty of treatments for diabetes. We should be able to find a protocol that's going to work well for our patient. And the ADA called out this year specifically that we should be choosing glycemic treatment plans that support weight management goals, not just glycemic goals. So we're really having that dual function of let's focus on weight and glycemic goals when we're treating type 2 diabetes. And so we've talked a bit about incretin-based systems today. Kathleen talked about the DPP-4 inhibitors versus the GLP-1 receptor agonists. And yes, these are all incretins, but they actually have pretty different effects when it comes into the management of diabetes. So while they follow the same pathway, I want to call out the DPP-4 inhibitors marked here in blue. When they are being utilized, they are going to cause what I call high physiologic effect or a slight increase in the GLP-1-based incretin effect. So you can get some lowering of postprandial glucose. You'll have very minor effects on glucagon. You're not going to see much effect on weight, and you'll have a mild effect on glucose. But the DPP-4 inhibitors currently do not have any extra glycemic benefits. When you use a GLP-1 receptor agonist, and now we have our first twin-cretin dual-GIP GLP-1 receptor agonist, you're now having a pharmacologic effect on this incretin-based system. And so now you're getting a more potent effect, which will include lowering of fasting and postprandial glucose because there's a stronger effect on glucagon. You're going to see more side effects because it's a pharmacologic effect of that system. But now you're going to get more robust glucose reduction. You're going to start seeing weight reduction, and we're also seeing extra glycemic effects. And I think these are important to recognize that while they're in the same system, they're really used with different targets in mind. And this is just the beginning. We're going to be seeing multiple other combination incretins that are going to be coming in the future. So this is the beginning of an exciting time. That being said, we've had the GLP-1 receptor agonist for 20 years. So we have had plenty of time to be identifying safety signals. And we know that these agents can be used. And you saw the meta-analysis in terms of benefit and safety. Now, I want to call out these agents specifically as it comes to the ADA standards of care. The ADA standards of care now recommends that all patients, when they're diagnosed, have diabetes education, care. on, say, muscle mass or bone mass? Certainly, we have not seen any kind of signal with medullary thyroid cancer. Are we going to see it if we have more people use it? That's unknown. Will the risk of pancreatitis or pancreatic cancer bloom? I think, again, that's unlikely, but again, these are things we're watching. On the positive side, are these agents going to have additional benefits that we don't know about, such as neuroprotective effects, more explicit effects beneficial in the kidney and on the liver, and maybe even effects on addiction? And so, again, these are still unanswered, but there are exciting data coming from it. I do think in terms of our... If you're only relying on this medication alone and you stop this medication, you should anticipate that weight and glucose will climb again. That's why we really need to double down on the important effect of comprehensive care and make sure that we're using these agents along with other self-care behaviors and lifestyle interventions so that patient is maximizing their benefit and not relying on the medication alone because we want them to be successful and on the least medications long-term as possible. So today we did a number of things. We talked about type 2 diabetes requires a tailored approach to make sure that we can maximize patient engagement through education, treatment, planning, and follow-up. This comprehensive approach will integrate lifestyle modification, self-care behaviors, and psychosocial considerations, and that these things line very well with osteopathic medicine and osteopathic principles. When you're using pharmacotherapy, we should consider patient's individual risk factors, preferences, and priorities when we're selecting an appropriate agent. And the current guidelines recommend GLP-1 receptor agonists, particularly with proven benefits, for additional benefits beyond glucose, including cardiovascular disease, chronic kidney disease, and evolving in metabolic-associated liver disease. And the literature supports outcomes for these agents, not only for diabetes, but also in these special populations. And they're reflected in current consensus statements and will be reflected in future guidelines. So I'd like to welcome Kathleen back because we're gonna present a couple of case scenarios and then have an open discussion about how we approach these patients, particularly as we look at treatment options and optimizing care with the patient in mind. Kathleen will present the first case, and lead the discussion, and I'll present the second case. Thanks, Jay. This case is a 42-year-old male with type 2 diabetes. He is employed in an office setting. He has had diabetes for five years, starting at the age of 37. He has obesity. He has comorbid anxiety, depression, and reports loneliness as well. He also has an extended history of hypertension and also has metabolic liver disease with a Fib4 score of 1.39. He reports suboptimal exercise and eating habits, and his A1c is 9.1%. So certainly there are a number of challenges here, and really trying to break this down into the individual elements where we can intervene are really important. His current medications are glipizide, metformin at 500 milligrams twice daily, and lisinopril at 10 milligrams daily. So how can we most effectively manage this patient? And ideally, we want to try to hit on multiple different areas of his life and his health that are likely to be impacting all of these health conditions. So first of all, we're, of course, going to emphasize optimal lifestyle habits and some of these comorbidities that can impact his ability to achieve healthy eating habits and activity. And one of those barriers is, of course, his mental health. And so top of mind for me, at least, is to make sure he has adequate support in this regard, referring him to a mental health specialist such as a psychologist, and also potentially to a dietician, and in particular, a diabetes care and education specialist, as Jay mentioned earlier, is really critical. And we also should acknowledge that that diabetes educator is not just an educator. They are there to provide support as well. We should also think about the dual efficacy recommendations for pharmacologic interventions of not only lowering the A1C, but implementing treatments that can help patients optimize their weight. So in this case, glipizide is a good agent for many people, but it really has limited durability in terms of long-term effectiveness, and it can make it more difficult to lose weight. And so we can think about discontinuing that in favor of agents that are going to have both A1C reduction and weight loss benefits. In particular, a GLP-1-based therapy is now considered the most effective glucose-lowering approach or therapy, depending on the type of GLP-1 used. And SGLT2 inhibitors also will have significant A1C lowering and some modest weight loss benefits. So because his A1C is so far above goal, if we're going to be discontinuing the glipizide, we'll need both of these medications. And finally, we want to optimize his blood pressure. Typically, patients will need dual or even triple medications. And so adding a thiazide type of diuretic is very effective, and this can be used in a combination pill to improve adherence. On the subject of general medication adherence, one of the concerns with a complex regimen is whether or not patients can stick with this long-term. So that support piece is really critical and helping patients to understand the long-term importance of this is really important. So here's how it went with this patient at their 12-week follow-up visit. They've actually lost 10 pounds. So first off, I would just congratulate him. This is in no doubt due to changes in therapy, but also would want to congratulate any changes that he has made with his diet and exercise. Turns out he has started walking, and he's still struggling with his diet, however, because he's using food as a coping mechanism. So again, undergoing some counseling can be helpful and encouraging the follow-up in that regard. He does note, he doesn't think that the counseling has helped much. So in this case, you could also consider actually pharmacologic intervention, and he was started on an SSRI. His current A1C is 7%, and I would also acknowledge that with the ongoing weight loss, this can help facilitate further therapeutic lifestyle changes because they can become more functional and actually provides an important positive feedback. So overall, he's improved, but recognizing that diabetes is very complex and addressing all of the comorbidities will really be important. So Jay, what are your thoughts about this patient? How do we balance glycemic control and all of these comorbidities? Yeah, well, first of all, I would want to highlight that the patient came when they were feeling down and not feeling successful and asked for help. So they get a kudo for that. And with some very effective medication changes, quite honestly, simple medication changes, the patient's now on a positive pathway, and boy, giving that person a high five, even though things are not all quite in line yet, is gonna be really reinforcing. And it highlights that kind of dual directionality of diabetes and mental health conditions, because I think when you're feeling down, it's so hard to manage diabetes, but if you could address mental health, you could have better self-care, or if you're able to get better control of your metabolic disease, sometimes your mental health conditions feel less burdensome. So I think being able to address the things that you did were really successful. And you might actually have had a moving A1C goal over time. It might've been that the first goal, first visit would be, let's just help you get the support you need. Once we have the support, then we can set an A1C goal. Now, this person had 10 pound weight loss and a 2% A1C reduction in 12 weeks. That's amazing. And so they're not gonna continue to have that path. So now it would be, how do we continue to be successful when you're there? And I think you talked about some very specific medications about using a GLP-1 and an SGLT-2, and quite honestly, using them together, because the person was at least 2% from a goal, and you're gonna need multiple agents. So I think that was really good. And now you can also say, now your weight is actually gonna be more beneficial. That's gonna feel more positive for him. And as you start to look at fine tuning meds, you can talk about other comorbidities. How is this gonna help your heart? Is this gonna help your kidney? Could this help that metabolic liver disease, which is amazing that someone did the FIB4, because it is recommended by guidelines for us to be doing it. So I think that this is a really positive step for this patient. Yes, I completely agree. And when you are thinking about both glycemic management and management of mental health and optimizing weight, you are in fact addressing all of these elements as one. Do you feel like there's an optimal approach? Really, I think there's a tendency to say, okay, this is everything that you are doing wrong, but how do we flip the script on that and actually maintain sort of that positive interaction that helps to motivate the patient? Yeah, boy, I think that is the magic, right? That's part of chronic disease management. So I actually always start with, managing diabetes is hard. We did a study that showed it takes about three hours per day to do all the self-care behaviors as it relates to diabetes. So that's like a significant commitment for anyone. And so I often will say, look, there's a lot of things we need to be doing. You can't possibly do them all every day. What are the areas that are gonna be easiest for you to implement? And start with those things first. And then I am just very gracious with high fives, smiley faces, notes that go home with patients to say, great job, not just on the product, but on the process, because it's that ongoing work that is really the diabetes self-management. And I think patients really appreciate when their efforts have been recognized, even if it's not just about the numbers. Yeah, in fact, I feel like sometimes I am a cheerleader and less so of a physician, because this is an ongoing process where that really support is needed. And we don't wanna get into a situation where we're going to kind of use threats of, oh, you're gonna lose your vision, or having them understand that there are risks and benefits, but also taking into account that this is a real person with real feelings and they have, and really engaging them in their care. Do you think, and you mentioned earlier that addressing his mental health, and I totally agree with that, is really job number one, because it has that impact on behavioral health. Have you seen much benefit in using pharmacologic therapies? What is your approach there in patients who have this sort of dual challenge of diabetes plus mental health comorbidities? Yeah, so I think in the primary care space, you really should be looking at a multi-component approach. So including pharmacotherapy, physical activity, and counseling. And again, a patient will kind of determine their readiness for each of those things. I do remind people regularly about the power of physical activity and in terms of particularly depression. And then I think if you're seeing them in the diabetes space reminding them that it is hard to do multiple things at once. Each of those conditions require a lot of work and then be kind to yourself. And if you're having a harder time, I actually use the word diabetes vacation. It sounds like you had a diabetes vacation and I understand you had other things going on. I welcome you back to come back from vacation when you're ready, and I'll help you kind of get back on that diabetes track. So I do think being kind in that process, recognizing the comorbidities, but letting them know that this has to be a priority because it's too much of a slog to try to do both conditions at once. Yeah, and that really speaks to the need for that team. You may not be able to do it all. I know I can't do it all. And so I really appreciate having, every patient has their primary care provider and then the other team members as needed. Great points. And thank you so much for sharing that case. So we have a second case I'd like to discuss. This is a female with type 2 diabetes. She's currently 65. She is retired. And as many of our retired Medicare patients, has a very limited income. And that's been an issue as it relates to kind of medical management. She is widowed, lives alone with two grown children, loves living with her family, admits that she sometimes is an occasional smoker and has tried to quit smoking. Has tried to quit several times, but it just keeps coming back. She is slightly overweight with a BMI of 27. And notably she has comorbid chronic kidney disease. And I wanna highlight that both the EGFR and the UACR were measured and are both abnormal. The EGFR is 40 ml per minute and the UACR is 320 micrograms, milligrams per gram. She's currently taking Metformin 500 milligrams twice a day and Lisinopril 20 milligrams daily. And her last A1C is 8.7. And she's familiar with kind of some treatment goals and feels like she's taking these medications, she's trying to do the work and really has not had the benefit that she'd like to see. So as we think about this patient, I think it's important to recognize what are her daily struggles and how do they interface with chronic disease management? So certainly she may be busy taking care of her children, probably not her children, maybe her grandchildren. Certainly cost of medications has been an issue and we may need to consider that. And she is worried about covering the cost of more medications. And she has some comorbidities that do affect her risk, including smoking cessation. So we could consider doing that first, considering about pharmacotherapy. And we actually talked about a lot of things with this patient and she felt like, I just need to have something that's going to tip the balance here because I want to see my A1C lower. I certainly don't want to smoke, but I don't want to gain weight and I'm worried that I'm going to gain weight. So we talked about the risk benefits and actually recommended a GLP-1 receptor agonist, but we also used what was preferred on her formulary because we wanted to make sure that we were respectful of her cost. We do have a happy report back, you know, at 12 weeks, she actually lost 13 pounds and she said, this is it, that's fine. I am fine to quit smoking now. I'm not worried so much about the weight gain. And while we prescribed a nicotine patch, she actually only used it for two weeks and then felt like she was on top of it and didn't need the patch. Now she did have some initial symptoms starting with the GLP-1 and even with the education that we would often give with that, she said she felt some nauseousness, increase in acid reflux and some diarrhea. So we talked about the importance of modifying eating so that she could tolerate this medicine better, but also we took our time with dose escalation. And so we said, you know, start on the first dose of the medicine when you're not having any side effects, we could go up. Now she still had some side effects. So we really did another visit with both myself and the educator to talk more about modifying eating habits further, particularly eating half of the meal and waiting 20 minutes before going to the second half of the meal. Certainly we timed the medication to be given at night in this scenario. These medicines are given, particularly the long acting ones, independent of eating meals. And then she stayed up with hydration and then reducing some fat in her diet. And happily, she also had an A1C down to 6.8%. And for her, that combination of lowering glucose and A1C was really motivating for her. And now she's feeling much more in charge. So Kathleen, I'd love to hear your thoughts. This is a person who had an elevated A1C on oral therapies, but does have chronic kidney disease. What would you set as your A1C goal? How do you take in the comorbidities into account? Right, so that is a really important question. The A1C goals are individualized. And as you pointed out earlier, the goal can change over time depending upon a number of different factors, like patient's expectations and ability to achieve all of the things that they need to do to achieve them. In this case, I would discuss with the patient what would be feasible in terms of diet and exercise and medication taking. Since she's really only on one therapy, we can more safely add in medications to achieve a lower A1C goal without causing undue hypoglycemia or weight gain. So I think that should be considered in this case. The other thing to consider is how likely is she to benefit from tight glycemic control? And we could argue that because of some of the comorbidities like chronic kidney disease, that perhaps the actual benefit of glycemic control itself may not be there. However, if I can achieve an A1C of 7%, I still might go for it in this patient. But keeping in mind that we're using therapies that can optimize her comorbidities and also acknowledge some of the other limitations, like she may have significant income limitations and taking some of these newer medications. And then also whether or not she can even intolerate them. So maybe on my first visit, I might try to achieve an A1C of 7.5% if we can get there, but getting to under 7%, I would not have concerns and I wouldn't loosen her glycemic control now that she has achieved it. Yeah, I think those are really important points and kind of evidence-based in terms of kind of the A1C goal. I do like the idea of weight loss for chronic kidney disease that also has some benefit. How about the use of an SGLT2 inhibitor? Where would that fit in this management for this patient? Well, yes, it's a really important question and we should acknowledge that with her EGFR of less than 45, we wouldn't expect a lot of glycemic benefit from the SGLT2 inhibitors. And because of that, we might not, you know, necessarily use it specifically for glycemic control. However, there are well-established benefits in patients with chronic kidney disease in terms of progression. We want to make sure that they're on an ACE or ARB, and that dose is optimized if possible, that their blood pressure's optimized. But in addition to that, if it's feasible, an SGLT2 inhibitor can delay the progression of chronic kidney disease. So it can be part of the conversation. Whether or not it's something that she can afford is a whole other question. And you've already addressed a couple of times some of the ideas of looking at social determinants of health. Certainly, how do you start this conversation with patients? Is there anything else you want to add for this case? I like to start with open-ended questions. What are the things that make it difficult to achieve your health goals? And when it comes to starting new medications, I always want to know how difficult is it for you to forge your medications? And just, you know, have they had prior experiences? Are they, you know, is this a barrier for them? And oftentimes, you know, we can prescribe something. And as it turns out, they have to make the choice between, you know, their GLP-1-based therapy or their SGLT2 inhibitor, or in some cases, they can't afford any of them. So that's my general approach. And, you know, incorporating social workers, other, you know, members of the care team, sometimes involves pharmacists, can be really helpful too. Yeah, I think those are all important. And I think as you start to do a team-based approach, you're also going to be able to help things such as health literacy and numeracy, because it's often our appointments are so fast that it's quite hard to be able to have that addressed. And just another shout out to whether that's community health workers or diabetes care and education specialists or dieticians, they actually can also help us make sure that our patient does have a proper understanding of their condition. So I guess one last question for you is, this patient had some side effects with the GLP-1, and then even with some coaching, still had some side effects. How often do you see this? And would you add anything in terms of how to tolerate those side effects? I think this is a really great example of, you know, of the real world. And in the clinical trials, we had really frequent contact with patients and really can try to provide ongoing support, but in the real world, it's not always the case. And so I try to work with the patients and sometimes keep them on lower doses and really just emphasizing that, you know, what dose can you tolerate? What are some of the things? And really trying to assess the pros and cons and the benefits versus, you know, some of the limitations that each individual has made. And sometimes we can't, you know, keep patients on, you know, any dose, but it's really good to be able to understand what can they tolerate and then just go very slowly. Yeah, and I think I love what you said there. And I actually, when we talked in the case, take your time with these agents. We have long thing, this is a long-term game. So we want the benefits of them, both glycemic and extraglycemic. Take your time with titration, do the education upfront. I've actually, I'm totally happy to give them the worst case scenario upfront and have them come back and say, oh, this was so much easier than I thought you said it was gonna be. And then they're happy. And I think that's worth it. And I would also highlight that this is anecdotal, but I am surprised at how often I can switch between GLP-1s. And even though they have the same side effect profile, people have different side effects. So don't give up on the class if you have a problem with one. I think you could certainly tolerate a different one, but I think it's worth giving it a try, particularly if they can afford it. As we start to wrap up today, I'd like to see, Kathleen, if you have any closing comments in terms of the role of GLP-1s in a multifaceted approach for patients with diabetes and comorbid conditions. What are your take-home messages? Yeah, so I think what we're seeing with this class of medications is while they can't cure diabetes, they can really impact multiple comorbidities, including glycemic control, weight management, blood pressure, lipids, and even a number of growing comorbidities. And it can be really one of the most important tools that we have in terms of pharmacotherapy. Yeah, I love it. And I just wanna highlight that the days of treating glucose only, the glucose center approach, can be behind us. We have now agents that lower glucose, but also provide additional benefits. And in patients with diabetes and comorbid conditions who are on multiple meds, anytime we can provide medications that have extra glycemic benefits, particularly those that are related to serious complications such as heart disease and kidney disease, but can provide benefit for those conditions, those patients getting that dual benefit can really be beneficial. And weight loss is a weight-centered approach, which ADA now recommends as part of our plan, has also be a priority with these agents. And because of their glucose-dependent insulin secretion, you're able to get lower A1Cs with less hypoglycemia. So if you're not using them already, you have new indications to use them that are guideline-based, and we hope that you've enjoyed this session. All right, good evening, everyone. We hope you're doing well. We hope you enjoyed the program. Kathleen and I are delighted to be with you tonight. And I just wanna, questions are coming in, and I want you to keep sending them in. Kathleen, I'd love to just kind of start with two very basic questions. Who is the ideal patient for a GLP-1, and who is not the ideal patient for the GLP-1 class? And then we can get to other specifics. Hi, Jay. Yes, the ideal patient for a GLP-1 would be anyone who is needing additional A1C lowering with or without metformin therapy now, using a patient-centered approach as well. And in particular, those people who need to lose weight. And also those individuals who have certain comorbidities, particularly cardiovascular disease or at high risk for cardiovascular disease. Those are the ideal candidates. But I think we're seeing that this class of medication can be used more liberally, more broadly than we have previously. In terms of those individuals who are not the best candidates, I think we have to think about certain contraindications like potentially pancreatitis, gastroparesis, people who really don't have good options for, in terms of affordability, and individuals who may not have any of those other comorbidities. So that number has, I think, narrowed over time as we've become more comfortable with these agents. Yeah, wonderful insights. And if you looked at the ADA standards of care, all pathways include GLP-1 with the exception of heart failure. So I do think it has a primary role in most patients with type 2 diabetes. And I love what you said about, in terms of those who are not good candidates, those who can't afford it may not be good candidates either, as well as those that have a compelling reason that maybe they would have too many side effects, such as gastroparesis, pancreatitis. So as we think about this, one of the things that we see a lot are people are pretty excited about the weight loss associated with this class. How do you navigate this with your patients when they're successful? And what's been the experience with weight regain if they try to stop it? Yeah, so really interesting two sides of that coin. And I think even more so than with any other concomitant therapies, we're able to peel off other medications that are being used for glycemic control. We're able to, if they're on insulin already, we're often able, maybe not necessarily discontinue it, but really reduce the insulin. So we have to be mindful of that because that is more of a chronic as a loose weight. I've had occasions where we see such great weight loss that, you know, and glycemic lowering that you have to even think about peeling off maybe their metformin or reducing their dose of metformin just to simplify their regimen. And then on the flip side is we have pretty clear evidence that patients do regain weight after stopping these therapies. Now there are mitigation measures in terms of implementing therapeutic lifestyle changes that can minimize that effect. But I think for the majority of people, we have to realize that that is likely if they are not able to implement really stringent lifestyle changes to prevent that. Yeah. So we have a one that's coming here that drives me crazy, not to get the question, the answer to the question. So what advice are you giving your patients who are anticipating needing surgery? How long are you holding the GLP-1 in advance and what are you telling the patient? Yeah, so this is gonna be institution specific. I think most institutions have their policies and what they've worked on, you know, usually through a multidisciplinary effort. And it's definitely an ongoing process in terms of evidence. Currently, we are having them hold a dose of weekly agents and likewise, you know, at least a dose or a day of once daily GLP-1s. And I think though that we really wanna have an individualized approach with patients who are on these agents more chronically are less likely to have the prolonged effects of gastric emptying. Also considering those patients who have other, you know, underlying symptoms that might be suggestive of residual gastric emptying. But the science is definitely evolving. We're just beginning to uncover what could potentially be these, you know, potential risks of surgical procedures and gastric retention. Yeah, and we're always trading that off with if we really were gonna follow the physiology, we would hold many weeks and then they'd be hyperglycemic for surgery and then they'd be canceled. So we gotta find that balance. So I'll take the next one. There's a question about what recommendations the management for these agents in people that have temporary problems getting refills. And boy, that was a real challenge last year where people couldn't access. And I guess, and I wanna hear your thoughts as well. I certainly am not a fan of jumping from one to the next to the next. I feel like that gets rather complicated, especially if it's not a permanent switch. We would down titrate and then up titrate to maybe make the dose last longer if there was a problem with dosing. We would have occasionally samples. But I think that ultimately, things that we can do to prevent that are write three months supplies, make sure patients are not going right up to the end. And so I do think that you can limit some of that by writing more at a time. People that wrote monthly had a lot more breakups. Did you see that a lot in your practice with people having trouble getting GLP-1s? It was incredibly common this past year. I think the major shortages have really kind of gone away in the last month or two. I haven't had nearly as many patients come back to me who are unable to obtain their GLP-1s. And I agree with that strategy as dose titration either up or down, if relevant, can be one way to address. I was having to do a lot of substitution and that can be chaotic, especially if you've got prior authorizations and formularies to consider. Yeah. And we had a pharmacy team and they were awesome. So at one point I said, find all GLP-1 doses within a 60 mile radius, and they actually did it. And so we could actually send patients, hey, go to this city, to that pharmacy and get it. And again, that's a burden for many patients. I recognize that. But in crisis, sometimes you'll have to do desperate measures. Okay. So what do you think about compounding pharmacists for semaglutide and trizepatide by use mostly for weight loss is the question, but I think it would be relevant for diabetes as well. Yeah. So it's certainly a much bigger problem for people who are using them for weight loss. And also quite frankly, the patients with type 1 diabetes, many of them are overweight and it's off label to use just for type 1 diabetes. So they're subject to the same kind of constraints as those who are using for weight loss. And the official stance, I think from many of the professional societies is that first of all, we don't know which compounding pharmacies necessarily are accredited. So if you're going to go that route, you do wanna make sure you're using kind of the accredited compounding pharmacies. Even with that, the official stance is to really be very cautious with that. And I think most professional societies are warning against that, that there are, although they might be small risks, there are potential risks of using compounded pharmacies. Yeah. And the FDA, for those that don't know, has this stipend or this rule that if there's this critical shortage of drug, you can then start compounding. That has since been lifted, but FDA also has suggested not to use self-compounded pharmacies. So, all right. So there's a question I'll take and I'll get your thoughts as well. How long should patients use GLP-1 receptor agonists for weight loss if they're not losing weight? And the general rule is that three months is the amount of time you expect to see 5% weight loss. I will tell you that we give a little bit more grace to the GLP-1s because they're once weekly, many of them. And so at three months, you're really just hitting 12 half-lives and you may or may not have gotten that. But I would say if someone's three or four months out and they've had no weight loss and that's the reason they're taking it, you might have to reconsider it. What do you think? Yeah, I mean, that's more than enough time to see weight loss. Although some of the agents could take that long or could take even longer than that to get up to the full dose. So in some cases, you're going to have to do a trial of six to maybe even 12 months, depending on how long it takes to get up to the full dose. Yeah, good reminder, right? These medicines have to be titrated with side effects in mind. So I want you to envision, or maybe not envision, what are you most excited about for GLP-1s in twin incretins and future incretins for future uses, extraglycemic or glycemic? What do you think is exciting as the future comes? Well, yeah, so I think the most exciting part of this is really trying to recapitulate physiology, right? So there are multiple hormones involved with weight loss, glycemic control, and in particular, how the gut hormones interact with the system, with the autonomic nervous system and the rest of the body. So as more and more sort of combination types of dual agonists and triple agonists come out, we'll start to see hopefully much better efficacy and potentially we'll start to see some alleviation of improvement in tolerability and or just administration. So these are the exciting technology. There's other oral agents that are being developed in this class through other kinds of structural modifications that allow for oral intake as well. And to date, we have monoagonists, we have dual agonists, and there's triagonists coming along the way. And I think those that involve glucagon as well might really be quite an addition because I think it's gonna give us a chance to not only lower glucose and fat and glucose metabolism, but increase metabolic rate in a way that it may even stimulate more weight loss. So I think that's something that we're looking forward to. But let's say I'm gonna do the flip side of that. I have a patient that comes in and says, I've got, we'll just call it an addiction. I have this addiction. Can I have my Ozempic? How do you handle that? And I realize that there's a lot more information you need, but as people get ahead of the game here, how do you handle that? Well, I guess, yeah, that depends on what they mean by that. Certainly, these drugs have promise for all sorts of conditions that might lead to weight gain. But I think it's pretty clear that trying to evaluate and treat mental health conditions is going to help with overall glycemic control and behavioral modifications that will help the patient to become more successful with implementation and also the maintenance of these therapies. So for people who have anorexia, who have other kinds of eating disorders, this may not be the whole ticket to kind of helping them. Yeah, and while it's very exciting that there are many new potential uses coming, just like anything else, we'd want enough data to know that the risk benefit profile makes sense. And I do think sometimes we get caught up in the hype and particularly patients can get caught up in the hype and we wanna make sure that we maximize that safety. And so kind of go with what the data has supports. All right, so I think, are there any other questions coming in? This is your last chance for questions. If you had to leave one thing for our listeners tonight, what would you want them to walk away with? Well, that's a challenge. I would say, use these agents with the knowledge that the patient-centered care strategies in realizing that these medications can facilitate both glycemia and weight loss, the new sort of dual treatment targets for pretty much everyone with type two diabetes. And then in addition, what kinds of comorbidities that might steer you towards use of the GLP-1s versus SGLT-2s, for example. Excellent, and I would highlight that we've had these agents for 20 years. We have plenty of safety data and certainly for our patients with diabetes, you can hit multiple pathways of the pathogenesis, which means you can reduce medication load overall. Kathleen, you highlighted the common feature that when you add a GLP-1, if they're on insulin, you can often reduce it and then sometimes stop it. And that can be a home run for a lot of patients. And so don't be afraid of these medicines. These are medicines that can be very helpful. They have a great safety profile. And if used properly, they are a strong partner in our algorithm. So I want to thank everyone for joining us tonight. Please make sure that you follow the prompts for your CME credit. And please join other AOA programs on demand. Thank you very much.

type 2 diabetes

GLP-1 receptor agonists

guideline-directed care

glucose control

weight management

cardiovascular health

incretin system

insulin secretion

hypoglycemia risk

patient education

comprehensive management

holistic care