Optimizing Outcomes In Type 2 Diabetes: Integrating Longer Acting GLP-1 Receptor Agonists

Transcript Details This is a transcript of a continuing medical education (CME) activity accessible on the ReachMD network. Additional media formats for the activity and full activity details (including sponsor and supporter, disclosures, and instructions for claiming credit) are available by visiting: https://reachmd.com/programs/cme/optimizing-outcomes-type2diabetes-longer-acting-glp-1-receptoragonists/7415/ Released: 04/08/2015 Valid until: 04/08/2016 Time needed to complete: 30 minutes ReachMD www.reachmd.com info@reachmd.com (866) 423-7849 Optimizing Outcomes In Type 2 Diabetes: Integrating Longer Acting GLP-1 Receptor Agonists Reach MD Optimizing Outcomes in Type 2 Diabetes, Integrating Longer-Acting GLP-1 Agonists Narrator: SLIDE 1 0:2 You are listening to ReachMD. Welcome to CME on ReachMD, this segment, Optimizing 2017 ReachMD Page 1 of 16

Outcomes in Type 2 Diabetes, Integrating Longer-Acting GLP-1 Agonists. SLIDE2 00:12 This CME activity was developed through the joint providership of the University of Cincinnati and CORE Medical Education, LLC, and supported by an educational grant from AstraZeneca and Novo Nordisk. SLIDE 3 00:26 This segment will focus on understanding of the effects of longer-acting GLP-1-based therapies, particularly in the area of appropriate patient identification and management of potential side effects so that these longer-acting formulations can be used appropriately. The target audience for this educational activity includes physicians and other healthcare professionals who manage patients with type 2 diabetes Your host is Dr. Matt Birnholz, and our guest today is Dr. Jack L. Leahy, Professor of Medicine and Chief of the Division of Endocrinology, Diabetes and Metabolism at the University of Vermont in Colchester, Vermont. SLIDE 4 1:06 The University of Cincinnati is accredited by the Accreditation Council for Continuing Education to provide continuing medical education for physicians. University of Cincinnati designates this educational activity for a maximum of 0.5 AMA PRA Category 1 credits. Physicians should only claim credit commensurate with the extent of the participation in the activity. SLIDE 5 1:30 Dr. Birnholz has nothing to disclose. Dr. Leahy discloses that he has served as an advisor for Janssen, Merck, Novo Nordisk, Sanofi and Vindico SLIDE 6 1:41 After listening to this activity, participants should be able to acknowledge the continuing burden of disease associated with type 2 diabetes mellitus and the need for newer treatment options; discuss how incretin-based therapies may address suboptimal glycemic control and improve patient outcomes associated with current standards of care; based on their unique and critical role, incorporate GLP-1 receptor agonists as part of the treatment schema in type 2 diabetes mellitus; and assess the value of longer-acting GLP-1 receptor agonists beyond glycemic control in type 2 diabetes mellitus such as its effect on weight, the cardiovascular system, beta cells, the liver, and acute metabolic regulation. 2017 ReachMD Page 2 of 16

The goal of glycemic management of patients with type 2 diabetes mellitus is to maintain optimal glycemic control while causing as few adverse consequences as possible. GLP-1-based therapies represent an important advance in the treatment of type 2 diabetes mellitus, but there is a need for better understanding of appropriate patient identification and management of potential side effects, particularly with the longer acting GLP-1 based therapies. This will be a focus of our discussion today. Dr. Leahy, welcome to our program. Matt, it's a pleasure to be with you. Well, let's start with the basic primer to set the stage. What is the current situation in the US regarding diabetes? SLIDE 7 3:04 Well, I think every healthcare provider in the United States knows that diabetes, unfortunately, is exploding around us. the current incidence that we know of is almost 30 million people with diabetes in this country, another 80 to 90 million with prediabetes. You go to elderly folks, you can find an incidence of over 20%, and then certain ethnic populations it's even higher than that, so we have an explosion of the illness. The cost has also become extraordinary. There was a very important paper that was published a couple of years ago looking at the cost of diabetes in 2012, and what was identified is that 1 in 9 healthcare dollars in the United States are spent on this disease, and there had been over a 40% increase in the cost since 2007 2017 ReachMD Page 3 of 16

Well, tell us a little bit about those diabetes-related complications and the good news there. SLIDE 8 3:51 There's an important New England Journal paper that was published in 2014 that gave us real data on the incidence of cardiovascular complications and renal complications in the United States from 1990 to 2010. I think it actually caught people a bit by surprise because we thought that we were not doing that well with heart attacks and strokes, but what that data actually showed is about a 50% reduction in both of those over that 20 year time span. And I think in terms of other microvascular complications, we've seen also big improvements over the last 10 or 20 years. So, I think the message for us and our healthcare providers is, we're doing a pretty good job, we need to do better, but we're seeing really important impact for our patients. Yes, that's a great message. Why don't we shift now to a brief review of the guidelines for treating type 2 diabetes. What are the current standards of care? SLIDE 9 4:41 So that's a really complicated question because there's a number of organizations that give us guidelines and so it depends a little bit upon the organizations that you follow. I'm a big believer in the American Diabetes Association, and they give us standards of care every January. The most important one is A1c. And there's big a big change in the last few years. It's kind of individualized. We still think about many people trying to get below 7% but understand there are groups of people where that's just too aggressive, especially older folks and people who have a lot of other kinds of illnesses. We focus on blood pressure. And even though that's an evolving standard, I'm a big believer in the ADA standard of blood pressure less than 140/80. And lipids, equally important, tend think about an LDL of less than 100 in most patients with diabetes, although probably less than 70 if there is existing coronary disease. And we talk about a triglyceride of less than 150; although, to be fair, we probably focus less direct therapy to try and improve that. 2017 ReachMD Page 4 of 16

And of course with some of the trials that have been pivotal in looking at hypoglycemia as a factor, I think the ACCORD trial and some others, seems like that has become a big part of how we consider glycemic control now. So that is hugely important. If you had asked the average specialist 3, 4 years ago, we probably would have said the lower the better in terms of hemoglobin A1c preventing complications, focus less on the balance of risks of hypoglycemia. But what the trials showed that you mentioned, particularly the ACCORD trial, if these were performed in people with a very high risk of coronary disease or preexisting coronary disease; and if you push too hard with too many medicines, there's a risk you might actually cause harm. So again, I think the balance for most patients is an A1c of less than 7%, but if there's substantial existing disease, especially coronary disease, we might think less than 7.5 or even in a rare individual less than 8. The dominant issue is really prevention of hypoglycemia. So with this balancing act in mind as a concept, how has drug therapy changed over time for diabetes treatment? SLIDE 10 6:48 Oh, it's changed enormously. We seem to get a new class of medicines every year with multiple components of that class. And so along with all of those drugs, there's really been a big philosophy change about how to use them. And one of the really important examples of that are guidelines of treatment, which have come from the American Diabetes Association and the European equivalent, the EASD, SLIDE 11 7:14 When you look at those guidelines, what you see is everyone sort of agrees that you start with metformin as your first drug in most patients, but then when you go to a second drug, you have this enormous choice, and these guidelines essentially say that one is not superior to the other, at least in terms of efficacy. But now what they really want us to do is to understand there are many other parameters that are important and things we need to consider with patients. They include not just efficacy but what the drugs may do in terms of potential for hypoglycemia, for weight gain or loss, for side effects, for cost. 2017 ReachMD Page 5 of 16

So, Dr. Leahy, with this background information let's start to focus on one of the newer classes, the GLP-1 receptor agonists. Now, what are these agents exactly? This is a very important question. Within that complicated list of drugs that have come to us, I think we look for drugs with high efficacy, but also a profile of safety and acceptance to patients. And one class that's really had an enormous amount of discussion you identified as the GLP-1 receptor agonists. SLIDE 12 8:16 Now they, which are injected drugs, and related drugs that are oral called the DPP-4 inhibitors, they kind of fall under this umbrella of what's called incretin therapy because they act on an important biological system we have called the incretin system. And, what the incretin system is, it's important biology that regulates post meal blood glucose and lipid values. We eat a meal, we secrete gut hormones, the incretin hormones, and they regulate islet hormone secretions, so they promote an insulin response and they turn off glucagon when we eat in a glucose responsive fashion. Now, important as we think about the drugs, the hormones that are the incretin hormones are GLP-1 and a hormone called GIP, glucose-dependent insulinotropic polypeptides; and these very powerful hormones, once they're secreted, are metabolized by a serine protease called dipeptidyl peptidase IV. So what Pharma has brought us is drugs that either inhibit the activity of that metabolic enzyme, i.e. DPP-4 inhibitors that are oral drugs, or drugs that are pharmacological activators of the GLP-1 receptor, GLP-1 receptor agonist drugs. So they're kind of related but they're different, and they're different in that the GLP-1 drugs are more powerful than the oral drugs, and they also have a different clinical profile because while both of these, the pills and the injected drugs, will regulate those islet hormone responses, SLIDE 13 9:58 it turns out that GLP-1 receptors are expressed in a lot of other places in the body. And if you pharmacologically activate them, you get a different clinical profile. So, for instance, when you give a lot of GLP-1, you will slow gastric motility, which is good because that flattens a blood glucose profile through absorption. There are GLP-1 receptors which are in the satiety area of the brain, so if you give a lot of GLP-1, you can actually improve appetite and people can lose some weight. There are receptors in important insulin-sensitizing organs within the body, so if you activate them pharmacologically you can get an insulin sensitizing effect, and these receptors are present throughout the cardiovascular system so you can get vasodilatation; you can improve cardiac 2017 ReachMD Page 6 of 16

contractility; you can get really a pretty complicated profile of effects. SLIDE 14 10:54 On the other hand, the oral drugs, the DPP-4s, they're not as good generally at improving blood glucose, but also you don't get that same profile. You really don't have any weight reduction -- they intend to be weight neutral -- and you really don't have any of the common GI side effects that you might see with the injected drugs. If you're just tuning in, you're listening to CME on ReachMD. I'm your host, Dr. Matt Birnholz, and today I'm speaking with Dr. John Leahy, and we're talking about GLP-1 receptor agonists. So, to stick with the subject, Dr. Leahy, what GLP-1 receptor agonists are available specifically? Are there important differences between them or among them? SLIDE 15 11:31 Well, there are, and in fact, the number of these agents continues to grow. And in fact, it's interesting because among the GLP-1 receptor agonist drugs, there really seem to be some important differences. They fall into 2 groups. There are drugs that we think of as short-acting drugs, The classic short-acting drugs that are available to us is exenatide, which is a twice-a-day drug There is another short-acting GLP-1 drug that's called lixisenatide, which is a once-a-day drug. It is not yet available in the United States, but it's available in Europe and it's very far along in development for this country. And, then we have a number of long-acting drugs, one which is once a day which is liraglutide, and then several weekly drugs, weekly exenatide, albiglutide and dulaglutide are available to us. And there's actually a long-acting weekly drug semaglutide, which is very far in development, which will be coming to us presumably in the future. SLIDE 16 12:33 Now, the difference with those drugs is that both the short-acting and the long-acting drugs share pretty similar clinical profile in that you get some weight reduction; you have safety for the 2017 ReachMD Page 7 of 16

most part against hypoglycemia the possibility of some nausea and vomiting is a class effect; and the improvement in cardiovascular risk factors such as lowering blood pressure a little bit and maybe increasing cardiac contractility a little bit, that's all class effect. We tend to think about those in both the short-acting and long-acting, but the difference that separates the short-acting and long-acting is, remember, the short-acting are given just before a meal and have a relatively short effect and therefore have a very modest effect on controlling fasting glucose, and mostly what is helping controlling postprandial glucose with those agents is the slowed gastric motility. SLIDE 17 13:30 Now, when we go to the long-acting drugs there's much less slowing of gastric motility and therefore probably less GI side effects; but also, because the GLP-1 effect lasts so long, you have a much better improvement in fasting glucose and often a superior lowering of A1c versus the shortacting drugs. Also, those drugs tend to show better weight reduction. Excellent. And if we were thinking specifically, as an example, you talked from the short-acting to the long-acting an example would be exenatide from a weekly dose versus twice daily how does that borne out in the research when comparing them? SLIDE 18 14:07 I love that question because that's such a beautiful experiment someone can do. We have exenatide, which is a molecule that can be taken twice a day, and then we have the same exenatide which is reconstituted and now made into a weekly preparation. And a head-to-head study which compared these two showed really exactly the point that I was trying to make. So what you see is quite excellent lowering of hemoglobin A1c with both of these agents. I mean, really it's a testament to how good the GLP-1 drugs can be in terms of improving hemoglobin A1c. For example, in that trial people started with an A1c in the low 8s and came down into the mid 6s with either of these agents, but there was a superior lowering of hemoglobin A1c. It was more with the weekly preparation, better control of fasting glucose with the weekly preparation, again attesting to the longer activity of the drug, typically translates into a better lowering of A1c. There wasn't any difference in hypoglycemia and there wasn't any difference in the weight reduction in this trial. 2017 ReachMD Page 8 of 16

And has there been any evidence beyond exenatide itself? SLIDE 19 15:15 Well, there is. For instance, there's a trial of comparing albiglutide versus liraglutide. What you saw in that trial is that there was less GI side effects with albiglutide, but also less weight reduction, and liraglutide was superior in improving levels of hemoglobin A1c. Liraglutide, the once-aday drug, has been compared against the weekly exenatide drug and liraglutide had a superior lowering of hemoglobin A1c. SLIDE 20 15:43 And the latest trial was to compare dulaglutide, which is relatively new on the market as opposed to liraglutide, and what you saw in that trial is essentially they were pretty equivalent. They seemed to be the most potent in terms of improving levels of hemoglobin A1c, and there really wasn't any big difference in terms of the weight reduction potential or the side effects between those two. Excellent. It's been a really good review of the efficacy, but obviously the next natural question is: What about the safety concerns? SLIDE 21 16:10 This has been an enormously important conversation. As I said earlier, this is a really important biological system, so if one activates the system or fools around with the system, you have to be careful in terms of what might occur. So, one of the things that we think about in terms of incretin therapies, in general, is there's pretty good safety against risks of hypoglycemia. Here we have an insulin secretagogue that typically the injections and the pills don't come with a lot of hypoglycemia because of that biological fact where the hormone secretion is glucose regulated. Still, one has to be really careful because while that is true with these agents generally, you lose some of that safety if they're given along with agents where there is a risk of hypoglycemia. The classic example is using them with sulfonylureas or insulin. And so if you're going to do that, we typically recommend that people think about lowering the dose of the insulin or the sulfonylurea when you add one of the GLP-1 drugs and then kind of re-titrate when you're ready. 2017 ReachMD Page 9 of 16

SLIDE 22 17:12 The other issues, the major well-known side effects of the GLP-1 drugs are GI. I think many providers tend to think nausea and vomiting because of the slow gastric motility; but in fact, when you really look at these trials, you find there's an equivalent risk of diarrhea, which is kind of interesting, so one has to be aware of that. Most of the agents, it's fairly transient, and one of the things I think we've learned is there's probably less overall GI side effects with the long-acting drugs as opposed to the short-acting drugs. And there's a very interesting trial which compared the twice-daily exenatide versus the once-daily liraglutide really showing that once you get through the first couple of weeks, there's a reasonably clear differential in terms of less GI side effects with liraglutide versus exenatide. SLIDE 23 18:04 The other really huge conversation we've had in the diabetes world over the last few years is potential pancreatic side effects or complications related to both the GLP-1 receptor agonists or the DPP-4 inhibitor drugs. This started probably 6 or 7 years ago when we received some information from the FDA that they were receiving some reports of pancreatitis in patients who were taking exenatide. So our field has spent a lot of time thinking about that and trying to get specific information to understand if it's really drug related or it's just essentially an epiphenomena. And a couple of the things we've learned is that there isn't any clear difference in the risk of pancreatitis when you look at large database analyses usually, and more importantly, I think we've learned there's a higher risk of pancreatitis, in general, in patients who happen to have type 2 diabetes. And so, at least right now, our concerns over pancreatitis are relatively modest with these drugs. The bigger conversation and the one which really engendered a huge amount of concern was the possibility of pancreatic cancer, and it's based on some animal studies and also some human studies which came from a fairly limited number of investigators proposing that there was a clear potential risk of the incretin drugs for either pancreatic metaplasia or even frank cancer. The data, I think, is generally viewed as being far from definitive; but because of it, there have been a number of important meetings and, most importantly, a clear statement, which came from the FDA and the European equivalent, published in the New England Journal earlier this year that clearly stated they do not believe that there is a proven risk of either pancreatitis or pancreatic cancer with incretin therapies. And I think 2017 ReachMD Page 10 of 16

the wording of their statement is really hugely important. It states, Assertions concerning a causal association between incretin-based drugs and pancreatitis or pancreatic cancer are inconsistent with the current data. Current knowledge is adequately reflected in the product information and labeling. So I think most people in this specialty believe that these are safe and that we need to have vigilance, but these are safe in terms of pancreatic risks. SLIDE 24 20:26 A few other comments, we've talked a little bit about thyroid cancer mostly based on animal studies, and maybe, maybe a risk of medullary thyroid cancer. That's such a rare cancer. I don't think we really believe it. And probably the only take-home message is no patient who has known MEN 2 or a personal history of medullary thyroid cancer should get one of these drugs We've talked quite a bit about patients with preexisting renal problems. I think exenatide, be it twice daily or once a week, is cleared more by the kidneys than the other GLP-1 receptor agonists, and so the wording essentially is for exenatide, be it twice daily or weekly, that it should be used with caution in patients even with moderate renal impairment. I think for the other drugs, the longer-acting drugs, the product literature states no dose adjustment should be done. It can be used with caution in patients with renal impairment. But I think we're pretty comfortable in using these drugs in patients where there's even real stages of clinical kidney disease. And then the last issue has to do with cardiovascular. I think one of the real positives of these drugs is lower blood pressure, improved lipid profiles, maybe a little impact on cardiovascular contractility in a positive way. And I think we're all waiting to see if there's going to be any cardiac benefit that's associated with these drugs So given what we know then about efficacy and safety data, let's just pose the million dollar question, which is, when to use a GLP-1 receptor agonist? 2017 ReachMD Page 11 of 16

SLIDE 25 22:21 I love the question. And because of a specialty practice such as mine, we're using substantial amount of the GLP-1 receptor drugs, in part because they're very powerful and they have this clinical profile we talked about, which is quite attractive to patients, a low risk of hypoglycemia, maybe some weight reductions, some improvement in blood pressure, lipids So if you look at the official recommendations, they say you can basically use GLP-1 receptor agonists almost anywhere. They can be used as monotherapy, although not typically, but they can be used as the first drug after metformin, used as the second drug or another drug after another oral agent, or used either in combination with insulin or added to insulin. Now, for me, one of the most important times I think about these agents is if someone is on oral therapy, be they one drug or a couple of drugs, if the A1c is much above 8%, I think there's very limited possibility that you can add another oral drug and get your A1c to a goal of less than 7 if that's what you're trying to do. So we tend to think about at that stage adding an injection drug, and the injection drug could be a GLP-1 or could be basal insulin. And the reason I say that, there's been a large number of head-to-head trials of taking people who are failing either 1 or 2 oral agents and comparing the efficacy and the clinical profile of adding a GLP-1 receptor agonist drug or adding basal insulin. SLIDE 26 23:31 There's a very famous trial of comparing liraglutide, the once daily agent, as opposed to glargine insulin, which I think we're all pretty familiar with. The starting A1c was 8.2%, so kind of in that profile where I said above 8%. And what came out of that trial which was a little startling is that both of these agents did an excellent job at improving levels of hemoglobin A1c, and in fact, the overall improvement in A1c was a bit better in the liraglutide versus the insulin-treated group. And also, the people who got the GLP-1 drug, they had some weight reduction as opposed to some weight gain in the insulin treated group, and no real big difference in the rates of hypoglycemia. SLIDE 27 24:16 So since that time there's been trials of comparing basal insulin, usually glargine, as opposed to essentially all of the GLP-1 drugs that are out there. And I think, again, the message is pretty clear, which is either giving a GLP-1 drug or giving basal insulin is very powerful at improving levels of hemoglobin A1c when people are failing oral agents. And in many of those trials with the long-acting drugs, such as the weekly exenatide or the liraglutide or the dulaglutide, they actually had a superior lowering of hemoglobin A1c versus the basal insulin. Now, the second sort of major decision point we have in a clinic like mine is someone who comes on oral therapy along with basal insulin already having been started and still their A1c is not to goal. And 2017 ReachMD Page 12 of 16

we have to decide, what do we do now? Are we going to add meal time insulin? Are we going to add more drugs? What actually can we do to try and help the patient really optimize their treatment with their basal insulin? And what we've learned from clinical trials is that adding a GLP-1 drug to people who are already on basal insulin is actually magical and just has an incredible improvement in hemoglobin A1c. The first trial which really got our attention that did that was taking patients who were on metformin and glargine insulin, who had an average hemoglobin A1c in the low to mid 8s, and the trial was either optimizing the glargine dose because you ought to be able to do better than an A1c in the low 8s with people on basal insulin as you're more aggressive with it or to optimize the glargine dose and add exenatide twice a day. SLIDE 28 26:05 And what came out of that trial is the A1c improved to the mid 7s by optimizing glargine. But when you added also exenatide twice a day, it came to 6.7%, and it came with some weight reduction, and it came with no differences in terms of rates of hypoglycemia And a number of trials have shown the same thing. SLIDE 29 26:25 And what's actually come out of that that's really exciting is a number of companies are now developing, co-formulations where in a single pen, for instance, you'll have a GLP-1 drug and you'll have a basal insulin together so that all the patient needs to do and what the provider needs to do is essentially titrate this one drug mostly based on an insulin dose and a fasting glucose and get the benefit of having the GLP-1 drug at the same time. And there's now studies that have looked at one product, which is having liraglutide along with the basal insulin called degludec, which is not yet in this country. And when you look at the results of comparing, adding to patients who are on oral agents with an A1c of 8.3%, adding liraglutide alone, it got the A1c to 7, adding the basal insulin alone, it got it to 6.9; but when you use the preparation where both were in the same syringe, A1c came down to 6.4% with a relatively small incidence of nausea and some weight reduction. That's amazing. So for me, these agents are really best when we get to the injectable world, used either with or without basal insulin, and just they have stunning clinical profiles. Well, I want to touch really briefly upon as you talked about co-formulations and the injectables the concept of delivery vehicle seems to be in relatively rapid change as well. I understand that the FDA recently approved a new injectable delivery vehicle, a microsphere single-use pen, and that there are others in development such as an oral and microneedle patch formulation. What can you tell us about 2017 ReachMD Page 13 of 16

these particular developments, and how do you think that their introductions could change patient management? The future is changing, and I think it's changing in a way understanding the importance of delivery of medications to patients along with the clinical profile and the safety and cost and all of those things. So, for instance, the first weekly preparation we had of the GLP-1 drugs was exenatide, so we had a twice-daily exenatide, and it was reformulated into a microsphere more viscus kind of preparation so it would last for a week. The early injections were difficult to do. And so recently what the FDA has done is to approve a new pen for the weekly exenatide, which is a single-use pen, much easier for patients to use. The other thing you said that is just so exciting is the idea of, will there actually be a time where a GLP- 1 drug could be given not by injection but orally? And it turns out one of those agents that I mentioned earlier, semaglutide, which is in development, very far along in development, seems to be a very potent GLP-1 receptor agonist when given by injection. There are early trials that the company has talked about that it actually might be able to be given orally, and from my understanding, it's in Phase III treatment now, so far with really excellent results We've reviewed several different factors regarding GLP-1-based therapies from the benefits to the limitations, the efficacy, the safety issues, even the novel delivery vehicles that are on the horizon. But before we wrap up today, can you summarize for our audience some of the main learning points that we've discussed? Slide 30 29:45 So I focused mostly on the GLP-1 receptor agonists. I talked a little bit about the DPP-4 inhibitors, which are the oral drugs. And I think one of the ways to start thinking about this is these are actually based upon an important biology, a target which was why these drugs were developed, because this biology is wounded, if not broken, within type 2 diabetes. So we think about these drugs of really having actions that are similar to this incretin biology, and that is to promote better postprandial glucose control in part through initiating an insulin response and turning off glucagon and doing that in a glucose-dependent fashion. 2017 ReachMD Page 14 of 16

The other thing that we've learned there's just a huge biology attached to GLP-1 with receptors for that hormone expressed in multiple tissues throughout the body; so when you start to give pharmacological amounts of GLP-1, as we do with the injected drugs, you can start to see diverse other organ effects. Slow gastric motilities we talked about, so you can get some GI side effects. Throughout the cardiovascular system you get vasodilatation, lower blood pressure. You improve maybe cardiac contractility a little bit. You improve lipid profiles. You have a satiety effect because of the GLP-1 receptors in the feeding centers and maybe actually even improve energy utilization so you can get some weight loss. 37:13 I think why healthcare providers are so interested in them is they really come with a high efficacy. And in fact, head-to-head trials against insulin have shown that GLP-1 receptor agonists are essentially equivalent in terms of their ability to lower hemoglobin A1c, as good basal insulin profiles and studies. And they come with a slightly different sort of clinical picture so that unlike basal insulin, you can get some weight lowering; you don't have a lot of hypoglycemia; you may have some GI side effects. In terms of safety, the best known side effects related to the GLP-1 receptor agonist drugs are GI. Again, I want to point out that most providers think in terms of nausea and vomiting, which is true, but also you can have diarrhea. And that actually can pose a clinical profile in clinic, if someone's on metformin on one of those drugs, trying to figure out which of those agents might be causative of the diarrhea. But for the most part, the GI side effects, especially with the long-acting drugs, are pretty self-limited There's no hypoglycemia with the incretin drugs in theory because of the biology we've talked about, but that is not true when used with sulfonylurea and insulin, and one needs to be aware of that and sometimes cut back on those other agents when you're starting one of these drugs. I think the prevailing opinion right now is that there is a high level of pancreatic safety related to the GLP-1 drugs and the DPP-4 inhibitors. I don't think we have any data now that supports that there is a substantially increased risk of pancreatitis. Having said that, if someone got pancreatitis, I would certainly stop the drugs and not restart it. And I don't think we have any data supporting an increased risk of pancreatic cancer with these drugs. Slide 31 32:59 Who to use them in? I think when oral agents have been essentially exhausted and it really doesn't look like you're going to get someone to go by trying to work adding more oral agents, 2017 ReachMD Page 15 of 16

that's when we talk about an injectable. If it's the first injectable, I think we decide either GLP-1 or basal insulin. If someone who's on one of those injectables, either GLP-1 or basal insulin, adding the other to it can be extremely effective and really strong. And the whole idea of having one delivery device that has both the GLP-1 receptor agonist and insulin in the same thing I think is our future In terms of uses, there is one other issue that comes up in my practice periodically. Typically, patients who have professions who make them not able to use insulin the classic one would be truck drivers with commercial licenses and some of them can respond very well to GLP-1, get adequate control and avoid the use of insulin. Finally, in terms of who not to use them in, I think we have to be a little bit careful in terms of patients with renal impairment; although, our concern over that is lowering as we get more information about most of these drugs. They should not be used in pregnancy. They're class C. We would not use them in a patient with a history of pancreatitis or clearly medullary thyroid cancer. And if someone came to me and was having a lot of nausea or vomiting or even reflux symptoms, just had a lot of GI complaints, this would probably not be my first choice of drug to try. SLIDE 32 34:33 With that I very much want to thank our guest, Dr. Leahy, for taking us through this encompassing review of GLP-1-based therapies for patients with type 2 diabetes mellitus. Dr. Leahy, thanks again for your time. Matt, it's a pleasure. Narrator: This segment of CME is sponsored by the University of Cincinnati and Core Medical Education and supported by an independent educational grant from AstraZeneca and Novo Nordisk. To receive your free CME credit or to download this segment, go to ReachMd.com/CME. Thank you for listening. 2017 ReachMD Page 16 of 16