Priscilla A. Hollander, MD, PhD: I am an endocrinologist and a clinical researcher at Baylor University Medical Center in Dallas.

Transcription

1 Steven V. Edelman, MD: Hello and welcome to today s webcast entitled Where Are We now? A Clinicians Guide to the Use of Follow-on Insulin for Patients With Diabetes. I am Dr. Steve Edelman. I am a professor of medicine at the University of California in San Diego and Veteran Affairs Medical Center. And today, I am joined with two of my esteemed colleagues, Dr. Eugene Wright and Dr. Priscilla Hollander. Priscilla A. Hollander, MD, PhD: I am an endocrinologist and a clinical researcher at Baylor University Medical Center in Dallas. Eugene E. Wright, Jr., MD: I am Gene Wright. I am an internist and consulting associate at the Duke Southern Regional AHEC in Fayetteville, North Carolina. Steven V. Edelman, MD: We are going to start off today s program and hear from Dr. Gene Wright about psychologic insulin resistance and talking about some of the barriers patients have to accepting insulin therapy. Eugene E. Wright, Jr., MD: We are going to also talk a little bit about some of the strategies to overcome these barriers. First, let us set the stage by talking about the multiple therapeutic options that we have to address the progressive nature of type 2 diabetes. As you can see in this graphic, that from diet and exercise early on through the time and years, over a 10- to 12-year period of time, we have a whole host of therapeutic options. Most people recognize that at the time that we start with pharmacologic therapy, approximately 50 percent of beta-cell function has been lost. What are some of the barriers that patients have to insulin therapy? We can see a list of things that have been listed here. Fear of injection, fear of hypoglycemia, weight gains, feelings of personal failure, feelings of associating insulin with a poor prognosis. Also cost and concerns about fitting insulin therapy into their lifestyle, especially as it relates to more frequent monitoring. How often do you hear some of these when you are initiating therapy with insulin? Steven V. Edelman, MD: About every time. Eugene E. Wright, Jr., MD: As we look at groups of patients in this study, all of them type 2, about 3,800 patients who are not yet on insulin, but they were being considered, asked if they would be willing to consider insulin therapy. The split between those who were unwilling to consider or begin insulin therapy from those who were willing 58 percent felt that they just did not have the confidence to do that, as opposed to approximately 40 percent of patients who were willing to begin it, who felt similarly, and so on down the line from the feelings of personal failure. Again, that they somehow had failed in their behaviors, 55 percent as opposed to 33 percent who were willing to start insulin therapy. What are some of the reasons that once patients are on insulin, they may be nonadherent or omit doses of insulin? As you can see, we have a list here of different reasons. Either they are too busy, they are traveling, they have skipped a meal, stress or emotional problems and this is another very important one embarrassing to inject in public. So, these are the kinds of things that your patients are going through and these are creating the psychological barriers to insulin therapy. Steven V. Edelman, MD: I would like to interject, Gene. Another important aspect of this slide is that when someone with type 2 diabetes omits their dose, they do not suffer as much. They do not have major symptoms, they take it, they feel okay, they do not take it, they do not really feel that badly like someone with type 1 diabetes. Eugene E. Wright, Jr., MD: And type 1, you are absolutely right, because they are totally dependent on their insulin and when they are having any psychological barriers, it affects them in a much more significant way. Quality-of-life issues related to fear or hypoglycemia. Now, typically in type 2, we do not think of hypoglycemia as being either frequent or severe. But the fear of hypoglycemia on these patients really changes their behavior. It is an additional psychological burden on the patient. It may and often does limit the aggressiveness of titration of their therapy and certainly, as we have seen, can reduce their adherence to therapy. Omitting doses or not staying on the insulin over a period of time. A severe hypoglycemic event can increase their fear of hypoglycemia in the future and, as we will see in the next slide, can actually change their behavior.

2 In this study, what we are seeing is the effects of the mild hypoglycemic episodes, defined as generally a blood sugar less than 70, and that will be in the blue, versus severe hypoglycemia, which is less than 60, which you will see represented in the green. In this, you can see the changes in behavior that people had a result of severe or mild to moderate hypoglycemia. Most notably, if you look at the third bar over, the increased fear of future hypoglycemic events. If you had a severe hypoglycemic event with type 2, 84 percent of the time, people feared having a subsequent. Steven V. Edelman, MD: I think Priscilla would agree too that a lot of type 2 s, they do not even have that severe of a low, but they have one reaction and then it takes months and sometimes years to get them back to be a little bit more aggressive again. Priscilla A. Hollander, MD, PhD: It can, but I think it is some of the advanced type 2 s, who are on multiple insulin injections. The risk for hypoglycemia tends to be fairly high in that group. Steven V. Edelman, MD: I would not underestimate the issue of hypo in type 2 s. Priscilla A. Hollander, MD, PhD: I would not. Eugene E. Wright, Jr., MD: And for that reason, it is one of those areas that we really need to address. To recognize and address in the management and treatment of type 2 diabetes. Psychological insulin resistance is a term that we use that represents a complex of beliefs about insulin and insulin therapy. Some of the issues associated with that include fear that insulin is dangerous, concerns about self-efficacy or the confidence that they have in the ability to do this or their motivation to take insulin therapy. Hypoglycemia, as we have seen in the previous slide, and weight gain, and then the injection phobia. Patients may not be able to overcome this insulin therapy reluctance or psychological insulin resistance until these personal concerns are recognized and addressed. Steven V. Edelman, MD: I think weight gain is also a big issue, as you mentioned, and I think if you initiate insulin properly and we will talk about it the weight gain does not have to be of any great magnitude. So, I think it is all communication and applying insulin correctly. Eugene E. Wright, Jr., MD: So, as we think about this, we have to remedy this patient s misconceptions about insulin therapy and that may help us initiate insulin therapy sooner, have the patients persist with the insulin therapy, adhere to the therapy, and more importantly, intensify or titrate the insulin therapy if and when it is required. What are some of the strategies? We talked earlier about some of the strategies that we can use to help patients with these barriers. First, sense of control. What I like to frame it up with the patients is that insulin is controlling the diabetes and the diabetes is not controlling you. The insulin gives you the ability now to regulate your diabetes and control it and make it is much easier to live with this. There are certainly beliefs that diabetes has become more serious, and therefore you have advanced insulin. Again, I like to frame this in the concept of as you live with diabetes, your therapy has to change. Insulin is nothing but an additional therapeutic option that you have over time. One of the challenges that I have found is the sense of personal failure, and I try to overcome that by disconnecting the patient's behavior or poor behavior with the progression of diabetes. It is very important for them to understand that in time, if they live long enough with diabetes, they are quite likely to require insulin, with the key being that they live long enough with diabetes to require insulin. Steven V. Edelman, MD: It is all how you frame it, Gene. It is so true. Priscilla A. Hollander, MD, PhD: Well, it is. But I think that currently we do feel that if people do have the right treatment and this may ultimately include insulin that they can do extraordinarily well with their complications. I think this is a message Priscilla A. Hollander, MD, PhD: - that needs to go along with the insulin message. Steven V. Edelman, MD: People love to take vitamins. Eugene E. Wright, Jr., MD: Yes. Steven V. Edelman, MD: I want them to change insulin to vitamin I and then we are good. Priscilla A. Hollander, MD, PhD: I think the future is very bright.

3 Steven V. Edelman, MD: It has never been a better time to have diabetes. Priscilla A. Hollander, MD, PhD: Exactly. Steven V. Edelman, MD: When you look at our tools we have nowadays. Eugene E. Wright, Jr., MD: Great tools and great opportunities to manage and control this. Fear of hypoglycemia and weight gain are two others. Again, a strategy for weight gain is helping people understand that there are newer insulins. The insulin analogs that we have, have much less of a problem with weight gain. Starting insulin early along with lifestyle adjustments can mitigate weight gain. And the fear of hypoglycemia, which we have seen can be a significant motivator, again, using insulin analogs and giving people tools to treat and manage diabetes and avoid hypoglycemia. We know from our guidelines that insulin should be considered in all patients with type 2 diabetes where noninsulin antihyperglycemic agents fail to achieve the target glycemic control or when the patients has symptomatic hyperglycemia. And when I say symptomatic, I think about the patient with high blood sugars and the polys: polyuria, polydipsia, polyphagia. Therapy with a long-acting basal insulin should be always the initial choice in these patients. Now, we have guidelines from the ADA and EASD algorithm that list a number of treatment options for treating hyperglycemia. We can start with diet and exercise and pharmacological therapy and progress to insulin therapy over time. If we only think that the barriers to starting insulin therapy are on the patient, there is a concept of clinical inertia that can lead to poor glycemic control in patients with type 2. This is on us, as clinicians. Clinical inertia is the failure to intensify treatment in a timely manner. There is a delay in intensifying treatment with patients with type 2 diabetes that can lead to poor glycemic control and prolonged periods of hyperglycemia. It is these prolonged periods of hyperglycemia that leads to the complications that we see with type 2 diabetes. Patients can remain in poor glycemic control over seven years before intensification occurs with insulin and even as long with people who are on oral agents before adding another agent to get them to glycemic control. Steven V. Edelman, MD: Gene, you make a great point because we always talk about the patients being resistant, but if a clinician is not familiar and comfortable using insulin, I think that is a major part of the problem, sometimes more than the patient resistance. Eugene E. Wright, Jr., MD: The challenge for the patients, when you think about the barriers that the providers have if the provider, the clinician, is not comfortable with insulin therapy that really is picked up very quickly by the patient. Some of the barriers that we have for providers as initiating insulin is we think that it takes too much time, that it makes the management of type 2 diabetes more complicated. We do not have the resources. We, too, as clinicians, have a fear of hypoglycemia. One of the things that we have pretty much dispelled with the ORIGIN Study is that somehow, there is an increased risk of cardiovascular disease with insulin. We know that that is not the case. And then certainly weight gain and our perception that the patients will be resistant to insulin therapy. Steven V. Edelman, MD: That is true. Eugene E. Wright, Jr., MD: So, in conclusion, I think of insulin initiation as a process, not as an event. By that, I mean, we introduce the topic of insulin therapy early in the course of the management and treatment of diabetes, often well before the actual need arises. We introduce it as a part of the natural progression of the treatment and management of type 2 diabetes, not as a punishment for poor behavior. We set individual targets and goals for A1C and adjust our therapies over time to not only achieve these goals, but to maintain these goals. And when starting insulin, start with basal insulin once a day, at night or in the morning and we titrate to the fasting blood glucose. Steven V. Edelman, MD: Now it is my turn to tell you about follow-on insulin therapy, and this may seem like a biology or chemistry lecture, but I am going to try to bring you through the important issues that you are going to need to evaluate all of the new biosimilar follow-on biologics that are going to be coming to your clinic soon. This busy slide talks about the differences between chemical drugs and biologics and I am going to repeat some of this information later on. If you can remember that the chemical drugs are more in the category of generics and the biologics are in the category of biosimilars. So, first of all, size. You get really small size with chemical

4 drugs, very large, and I have a slide to show you the differences in some of these compounds, which are quite striking. The structure is a lot simpler with drugs where they are way more complex with biologics. Manufacturing is quite easy and straightforward with chemical drugs. That is why we can develop generics pretty quickly, but manufacturing is a lot more complex the larger and the three-dimensional shape of the molecule gets, and that is biologics. Characterization: You can characterize generics and chemical drugs extremely well. But when it comes to follow-on biologics and biosimilars, just as they are describing, they are similar, but the complex nature of these large molecules that are hundreds of thousands of daltons are very hard to characterize. In terms of stability, chemical drugs are very stable and biologics are not as stable. And then the whole issue of immunogenicity. That is a very important safety issue when we talk about followon biologics and biosimilars. The larger and the more complex structure that these molecules are, the more they are susceptible to antibody formation, and that is something that FDA and the European regulatory bodies are looking at carefully. Here is just a picture of a couple different molecules that you probably use every day. You can see acetaminophen is only 151 daltons and it is quite small, it is not very complex. It is very easy to produce and characterize. And then on the other end of the spectrum, you get a coagulation factor and it is over 260,000 daltons, and you can see insulin glargine on the upper right there, which is over 6,000 daltons. So, the more complex the molecule, the harder it is to replicate it and to produce a biosimilar. This slide emphasizes the importance of biologics. Biologics themselves, no matter what area of medicine you are treating, are becoming a more and more important part of our whole medical armamentarium. In fact, over 20 percent of the total global spending on drugs is due to biologics, and in 2002, we spent worldwide 46 billion, and in 2017, it is estimated to be over 220 billion dollars. You might think, why are many pharmaceutical companies developing biosimilars? Well, it is because we want to make these insulins more available to people who may not have access to them and to reduce the cost of medicine. It is basically that simple, and if you did not know this, worldwide, there are 40 insulins being developed and under consideration for biosimilars. Let me tell you a little bit more about what a biosimilar medication is. Biosimilars can be in many different areas of medicine. As we are talking about diabetes, we are really talking about biosimilar insulin. It is a copy of a commercially available biologic that was already produced by a company that developed the insulin, for example. The originator, the very first insulin, and then of course the follow-on biologics are the biosimilars that we are talking about. And they have to meet specific criteria, mainly safety and efficacy, but they do not have to be exact. In fact, it is almost impossible that they are exact. And there is other terminology. I have already talked about biosimilar and follow-on biologic. As you can see from the slide, there are a lot of different phrases people use, but I think the ones you are going to hear the most are biosimilar and follow-on biologic. Now, if someone says, I am going to use a generic and use some type of insulin phrase, that is actually not correct. You can say you watched this webcast and you can say generics only refer to really simple compounds like acetaminophen, metformin, ACE inhibitors, things like that. Now, this slide goes over a few more of the differences. It is a little bit of a repeat than that introductory slide that looked at chemicals versus biologic, but the bottom line is that the molecules are quite small with generics. They are complex with biosimilars. The manufacturing process is much more complex with follow-on biologics and biosimilars. The development and validation is much easier with generic compounds compared to biologics. And when it comes to administration, generics are typically pills and you just swallow them, but you get more complex follow-on biologics and biosimilars, just like their biologic counterpart, they are typically injectable agents. I think it is important, as a prescriber, to say I am not a chemist, I may not know how these things are produced, but I want to know if the efficacy and safety are the same as the original product. And I think that is important and that is the role of the FDA, especially for those of us seeing patients in the United States. And I think they really have to show evidence that it may not be exactly, but it has all the properties that you would expect from the original product, and I think that is important. And it relates to many different aspects. Talking to your patients in clinic, writing a prescription to the pharmacy, and knowing that you are going to get the same effect, the dose per dose relationship, etcetera. I think all of us in clinic are pretty busy, and to get into the details, some of which I am telling you on today s webcast, may not be practical. Now, this slide is pretty important because when you look at the different characteristics of these biosimilars and follow-on biologics, you really want to make sure the structure is similar, they function the same, and it all starts with early animal data and very important PKPD in humans. What is that? It is the time course of action of these insulin. Does it start to work in the same amount of time? Does it peak about the same time? And is the

5 duration similar? Because these are things that are important to us when we tell patients what time to inject it, what are the best times to check their blood sugars, when to expect hypoglycemia, if any at all. And then, of course, there is clinical immunogenicity. I have already talked about that. That is an important safety issue. Dr. Hollander will talk about some of the clinical trials when it comes to immunogenicity and also other safety features and effectiveness. I have seen the data at large meetings, but it is nice that it is now published and it will be interesting for our audience to see as well. This slide is the typical stepwise approach of evaluating a biosimilar, and it starts with early physiochemical characterization, then you get biologic characterization, then you have preclinical studies, and then you have Phase 3 studies, which are the large clinical studies before approval. And so, the process is very similar to the original biologic, but as I will say in a second, they have made it condensed so they can produce these biosimilars much quicker. This slide looks at a historical timeline of all the different insulins. Insulin was put into clinical use in the early 1920s. We have come a long way since then, and even up to year 2000, we pretty much just had NPH and regular. And since then, fast-acting analogs, long-acting basal insulins, and then just recently, our first basal insulin biosimilar follow-on biologic was approved. Now, there are some potential clinical uses for biosimilars, and on the upside, we know it is going to be more available to people. And if you are going to be on the hesitant side, there is limited published data, but I suspect that as these biosimilars become available worldwide, you are going to see more and more data coming out and presented in medical journals and our meetings. Immunogenicity is an issue that definitely was an issue with biosimilars in other therapeutic areas, like hematology, so I think the FDA and the EMA, the European Regulatory bodies, are keeping a close eye on that, and Priscilla will talk about some of that data. And of course, there is the delivery device. You could have a great biosimilar, but if it is an inaccurate or poorly functioning insulin pen, for example, then that may lead to issues as well. Let me conclude my section with a few important points. First of all, generics are small molecules, very easy to replicate, and they are typically oral, but biosimilars are not identical copies of the originator product, but they are extremely similar in many factors. They are safe and effective, as proven by clinical studies and approved by the FDA, and the FDA has established an abbreviated pathway, mainly to give incentives for pharmaceutical companies to develop safe and effective biosimilars to make them more available to people worldwide and reduce the cost of medicine. And finally, I think it is exciting that the very first biosimilar or follow-on biologic was approved in the United States as it relates to a basal insulin for the treatment of both type 1 and type 2 diabetes, and I think it offers many advantages, especially reaching many folks that may not have access to these newer basal insulins. But it also presents some challenges, and hopefully we will go through those and have gone through some today. Priscilla A. Hollander, MD, PhD: I am pleased to be able to present a new option for the management of patients with type 2 diabetes, follow-on insulin therapy. Now, insulin is considered the ultimate therapy for patients with diabetes, certainly for patients with type 1 and ultimately for most patients with type 2 diabetes. Let us start out about when to start insulin in patients with type 2 diabetes. Dr. Wright touched on this briefly, but we would like to go ahead with insulin in patients with type 2 when their non-insulin agents are not resulting in an achievement of target glycemia or they are having unacceptable side effects of non-insulin agents, and certainly diabetic patients who have challenges, such as advanced hepatic or renal disease, special circumstances such as steroids, infection pregnancy, hyperglycemia in the hospital, and severely uncontrolled diabetes. Now, our goal in developing new insulins is to develop insulins that mimic natural insulin function. This slide shows the profile of an indigenous insulin over a 24-hour period. And what we try to do is match that profile using bolus insulin and, of course, basal insulin. So, let us think a little bit about the basal/bolus insulin concept. Basal insulin suppresses glucose production between meals and overnight. It should cover about 50 percent of daily needs and it should provide nearly constant, and this is very important, 24-hour insulin levels. Bolus insulin is used at mealtime and should have an immediate rise and a sharp peak at one hour and is used to cover maybe 10 to 20 percent of total daily insulin requirement at each meal, depending on what an individual eats at those meals. I am going to focus on the role of basal insulin, and I consider it the foundation of diabetes therapy. We can use basal insulin in so many ways. It can be used as a monotherapy. It is used with oral therapy. It can also be

6 used with the injectables, such as GLP-1, and of course, basal insulin is used with prandial insulin. I want to focus on a very interesting study called the Treat- To-Target trial. If we go back to the early 2000 period, there was only one basal insulin available for treatment of diabetes. This was NPH. It had to be used twice a day in general, and it was not a 24-hour insulin. It was associated with hypoglycemia, that at times was unacceptable. It was at this point that we saw the introduction of glargine, known as Lantus, as a new insulin in terms of achieving a 24-hour coverage. This study looked at titrating glargine against NPH in patients over a 24-week period, and it showed that glargine was just as effective as the NPH in terms of achieving hemoglobin A1C. It also showed and made an important point that there was less hypoglycemia seen with the glargine drug rather than with NPH. So, from this point on, glargine became what might call the workhorse of insulin therapy. And it has been used in combination with other diabetes agents. This shows a series of studies done with DPP-4 inhibitors that were added to basal insulin, and there was improvement in glycemic control in each study. We have also seen the use of SGLT-2 inhibitors added to basal insulin in type 2 diabetes. It also shows that basal insulin has been utilized in combination with SGLT-2 inhibitors, in this case, a study of empagliflozin with two different doses added onto basal insulin in type 2 diabetes, there was significant improvement in A1C. Also, as we have seen with the SGLT-2 inhibitors, there was weight loss. This is an interesting slide in that it looks at the combination of glargine or basal insulin with the GLP-1 agonist. This is an area that is receiving great attention currently in terms of this combination being very effective in covering both prandial glucose and basal glucose. And there was improvement here as well, with the addition of exenatide. Again, looking at prandial insulin to basal. Further therapy does improve A1C level. This is perhaps the ultimate combination of insulin therapy. This is a study that looked at adding one bolus at the largest meal of the day and then adding, sequentially if needed, at the second meal of the day and possibly at the third meal of the day with improvement in glucose control. I would like to now change and look at studies that are important in evaluating the new follow-on insulin agents. As we know, BASIGLAR, or what I am going to call LY glargine, was just recently introduced into the United States, although it has been available in Europe for the past year. I know that physicians are going to have a lot of questions about the development of this insulin, its efficacy, and its safety. I am going to present the two seminal studies that were done to evaluate this insulin, one in type 2 diabetes and one in type 1 diabetes. I will also follow on with some studies that are done in another biosimilar insulin that is in development, but is not yet available in the US. This is the title of a presentation that I gave at the American Diabetes Association about a year ago titled Similar Efficacy and Safety with LY Insulin, which I am just going to call LY glargine, Compared with Insulin Glargine in Patients with Type 2 Diabetes. It is the ELEMENT 2 study. Now, this has actually been published with Dr. Julio Rosenstock as the first author. This shows the LY glargine development program. As Dr. Edelman has mentioned, the FDA has set up a course of development for biosimilars, and this shows that development in terms of LY glargine. And you start out with preclinical studies. You then move on to Phase 1 studies and then to the Phase 3 studies, which are the ELEMENT 1 and the ELEMENT 2 studies, which I am going to present. So, ELEMENT 2 study, which is LY glargine versus regular glargine in patients with type 2 diabetes and who were insulin naïve or previously treated with glargine. This was a 24-week study. Patients had a short run-in period and then were randomized either to glargine or to LY glargine. There was a titration period for the first 12 weeks, and then stabilization was achieved and the titration was stopped at 12 weeks, and then the study went on for the additional 12. There was a four-week follow-up period. Patients in this study were very typical type 2 s and could been on oral agents as well. This is ELEMENT 2 A1C level over time. There was a decrease in A1C that was rather nice, with a slope that started to stabilize at about 16 weeks, and this is when the titration studies were stopped. And at the end of 24 weeks, there was no significant difference in A1C results between the two arms. This was taken as a sign of non-inferiority, which, in essence, is what we might describe as a biosimilar insulin and that it has fulfilled the requirements for equal effect on efficacy. We see a similar finding for fasting plasma glucose. Again, an initial drop with stabilization at 12 weeks and then

7 continued on to 24 weeks with no difference of findings at the end of the study in terms of effect on fasting plasma glucose. Again, and this is going to sound very similar as we were talking about biosimilars, that insulin dose and body weight were also very similar. In terms of the daily basal insulin dose, there was no difference in terms of insulin dose between the two arms. We also can look at body weight, and again, there was no difference in body weight at the end of the study. And the data was further subdivided into patients in this study who were insulin naïve when they started the study versus those who had already been on insulin, and there was no difference in any of these parameters between the two groups, whether they had previously been on insulin or whether they were insulin naïve. And this was true for the A1C curves as well as the fasting plasma glucose. We look at here at risk for hypoglycemia. The incidence, again, showed no apparent differences looking at total number of hypoglycemic events, nocturnal hypoglycemia, and severe hypoglycemia. This was also true for event rates as it was for incident. This is an AE summary. It is a little bit more complicated. Again, there was no apparent differences in AEs, death, serious AEs, etcetera. There was special assessment of allergic events, because some concern about immune issues, but again, there was no difference and no difference in injection-site reactions. And I think we know who have been using Lantus, that occasionally you can see an injection-site reaction. One very important element, again, was the immunogenicity, and this slide shows us that as these patients were followed through the study with samplings at baseline and throughout the study, that there was no apparent differences in their responses, either proportion of patients with the technical anti-insulin glargine antibodies or incident of treated antibody response. So again, we have a very clean picture here in terms of results of this particular study. I am also going to look at the results from the type 1 study. This was called the ELEMENT 1 study, and this study has also been published. And this ELEMENT 1 showed safety and efficacy of LY glargine versus glargine in patients with type 1 diabetes. This was a longer trial than the trial in type 2 diabetes. It ran for 52 weeks rather than 24 weeks. Again, because of the nature of type 1 disease that it is an autoimmune disease, the FDA felt that longer studies and more closely looked at immune phenomena should be done in this particular group. However, like the ELEMENT 2 study, the hemoglobin A1C results showed no difference between the two arms, either the regular glargine or LY glargine. And change from baseline at A1C level was very similar, as shown in the bar graph as well. This is a very busy slide, but it looked at additional clinical assessments in the type 1 population. Daily mean blood glucose, no differences at 24 weeks and at 52 weeks. The same for the fasting blood glucose. The same for the insulin dose. The same for the body weight. The same for hypoglycemia, and the same for detectable antibodies. So we are getting the same story over and over here that there appears to be no real differences in the parameters that we are assessing, both in the ELEMENT 2 study and the ELEMENT 1 study. So, I would like to describe the type 2 study done with MK versus glargine in patients. This slide shows us the A1C level over time. This study had identical design to the study done for LY glargine. It included patients who were insulin naïve and it also included patients who were on insulin. It is a 24-week study. Patients were randomized either to glargine or to MK There was a titration phase during the first 12 weeks. There was a nice drop in hemoglobin A1C, which tended to stabilize at 12 weeks and was then stable to the 24-week point. At the end of the study, there was no significant differences between the two groups in terms of the effect on hemoglobin A1C, and the conclusion was that they had shown that MK-1293 was also not inferior to Lantus. Looking at the bar graphs, they did also assess the A1C response separately in patients who were insulin naïve and those who were on insulin, and the changes there were nearly identical. We can look further at the effects of MK-1293 versus glargine in terms of fasting plasma glucose. We again see changes initially secondary to the titration approach stabilizing at about 12 weeks and then at the end of the study were not significantly different. An important parameter of these studies is the actual amount of insulin that is used, and as in the LY glargine studies, for the daily glargine doses there was no difference here between the MK-1293 and the glargine, again confirming further similarity.

8 Additional information on a study on MK-1293 versus glargine in patients with type 1 diabetes was also presented at the American Diabetes Association meetings this past summer. The study done with MK-1293 versus glargine in type 1 patients was also set up in a very similar way to the ELEMENT 1 study. This just shows the effects on A1C for the first 24-week period of that study. There was initial drop in A1C during a titration and stabilization approach and then there was stabilization from about the 12th week on, and at the end of the study, there was no significant difference between the two agents. They also looked at the basal insulin dose, and although it does look like the two arms separate slightly at the end, this was not a significant change. And the average amount of insulin needed in the two arms, by patients, was of no difference. So again, for both MK-1293 and type 1 and in type 2, it was felt that they did demonstrate a non-inferiority with the use of MK This is a study that looks at the anti-insulin antibodies for MK-1293 in the type 1 group. Again, with type 1 diabetes, there is more concern about antibodies because of the nature of the disease. However, as was shown previously for LY glargine, there was really no difference in antibodies or significant differences in antibodies. In summary, LY glargine and MK-1293 versus glargine in people with diabetes in studies showed similar glycemic efficacy. A1C levels were similar, insulin doses were similar, there was no difference in fasting blood glucose or in hypoglycemic risk. In the ELEMENT 2 study, it showed no differences in weight. They also had similar safety and tolerability profiles. The overall AE and serious AE profiles were similar as were the antibody responses. So they do, at this point, provide another tool for hypoglycemia management in patients with type 1 or type 2 diabetes. Steven V. Edelman, MD: Priscilla, thank you for the presentation. You talked about the ELEMENT 1, ELEMENT 2 study. And that is LY glargine, which is going to be marketed as Basaglar. And apparently it is available right now. You talked about the similarities and there were a lot of similarities; were there any clinically relevant differences that our viewers would like to know? Priscilla A. Hollander, MD, PhD: No. I think the studies show that there were not. I think the studies were very well done; they hit the important parameters in terms of looking again at efficacy, safety, safety in terms of hypoglycemia and immune responses. The programs were done very well; they both used the guide that has been set up by the FDA and which you described in your talk. And so there really does not seem to be any obvious problems. Now, once an insulin gets into wide use, then of course sometimes there could be possibilities of seeing differences, but again, the clinical evidence is very good. Eugene E. Wright, Jr., MD: So right now, as a clinician, I could change from one dose of glargine to Basaglar, the same dose for dose change in patients with type 1 or type 2. Priscilla A. Hollander, MD, PhD: I think the studies would indicate that that is the case. Now all patients are individuals, and again, there are a number of insulins available currently that have been in the market, and sometimes when one looks at changing insulin, you would pay little bit more attention to the patient s program in terms of their monitoring. But the studies would indicate that overall, in a general population, they are similar and equally efficacious. When one does a new insulin in any patient, you want to make sure that they are perhaps monitoring a little bit more closely. Steven V. Edelman, MD: And being the first follow-on biologic basal insulin, there will be pharmacovigilance and we will have more data as time progresses. Priscilla A. Hollander, MD, PhD: I think that is very true, but it does look like a nice alternate choice here for patients with diabetes. Eugene E. Wright, Jr., MD: It is all about choice in patients with diabetes. I am going to talk a little bit about incorporating follow-on insulin into clinical practice using a case-based discussion. Our first patient is Edward, a new patient who has just moved to the area and comes to you for his ongoing care. In addition to type 2 diabetes, he has significant past medical history that includes dyslipidemia, which is treated per the statin guidelines. Hypertension that is well treated and well controlled, erectile dysfunction that has been controlled and treated with a phosphodiesterase inhibitor, recent diagnosis of background diabetic retinopathy, and a recent complaint of chest pain earlier that had been evaluated with a cardiac workup and was negative, and was treated for a gastroesophageal reflux with great symptom relief. His family history is normal for his mother, who died at age 71 of a stroke, who also had diabetes, dyslipidemia, and a significant family history of vascular disease. His father, age 77, is currently alive with a long-standing history of

9 type 2 diabetes, dyslipidemia, and hypertension. He has three children, ages 18 through 24, who are college or graduate school age and in school. His social history: Edward works as a manager for an auto dealership. He is variably active at work with no regular exercise program. He neither smokes nor drinks regularly but does admit to alcohol on the weekends. His current anti-diabetes medicines: he is on metformin extended release, 2 grams a day, pioglitazone, glimepiride, and canagliflozin. So he has a four-oral-agent regimen. His physical exam is as noted below, he has a BMI slightly over 31, his blood pressure actually is fairly well controlled, he has slight reduction in his pedal pulses and lowerextremity vibratory and pin sensation. Consistent with his diabetic retinopathy, he has scattered microaneurysms. Most notably, his A1C is 8.8 percent. Now, for discussion, how would you modify Edward s antihyperglycemic regimen at this point? You have four choices here. Either increase his glimepiride or metformin, increase both glimepiride and metformin, add a basal insulin or add a GLP-1 receptor agonist. So let us talk a little bit about how we contemplate therapy when you get to this point where you need to do something different. It is important for every patient with type 2 diabetes, as well as type 1, to set an A1C goal. And here we have some guidance from [the journal] Diabetes Care about what are the factors in determining that goal. For patients who are early in the course of their disease, relatively short duration, without significant comorbidities, the goal and the target should be less than 7 percent. As they get further along in the disease progression with significant complications or at high risk for hypoglycemia, we loosen that target goal up, but always trying to keep it less than 8 percent and using all of the therapies that we have available. We have some guidance for different therapies that you have seen earlier in the ADA/EASD algorithm for patients with type 2 diabetes, and we can look at the different therapies. Most notable in Edward, he is now on four oral agents, and we would agree that this is probably time to consider something else. As we have seen with Edward, when do we start patients on insulin? We know from our guidelines that when combination oral or injectable non-insulin therapies do not achieve the results of our target, we need to consider insulin. If there are unacceptable effects of non-insulin agents or side effects, consider insulin. And as we have seen in Dr. Hollander s presentation, patients who have advanced hepatic disease, pregnancy, special considerations, or hyperglycemia in the hospital, or glucose toxicity. So severe, uncontrolled diabetes. For Edward, he has some significant obstacles and barriers that we need to consider. His life concerns. He has developed a sense of personal failure with his lifestyles. He thinks that is why his A1C is not yet at the target. He is concerned about his finances and his college and tuition, and certainly on his oral regimen, there is a significant cost involved with that. He is also concerned about job security, as his auto line is not doing well and he needs to keep his job. There are several lifestyle information items. He has had several scheduled appointments with a certified diabetes educator and dietician but he has not been very good about keeping up with these. And he has consciously tried to avoid insulin because of his concerns that insulin was started shortly before his mother died, so he has some concerns about that. He also has concerns that he has a salesman at work who uses insulin therapy and has frequent bouts of hypoglycemia during the work day, and he is concerned that that may be an issue for him. Now, given these additional concerns that Edward has, how would that change your thinking about his antihyperglycemic regimen now, and what you would do next? Priscilla A. Hollander, MD, PhD: This is an interesting problem, and the question here is his A1C is at 8.8 percent how much of that is lifestyle? Dr. Edelman raised a point: is he actually taking all his medications? It is a fairly complicated regimen. So all of those things could be contributing to the fact that he is 8.8 percent; however, that is a fairly high A1C, and so he obviously needs a change. The question is, would increasing metformin or glimepiride, I am not sure that they would be enough to bring his A1C down into the type of goal we are really looking for. One might consider the GLP-1, but again, you have to look at the studies and say how much improvement do we see with adding GLP-1 to somebody who is already maximized on four orals? How much left is there that a non-insulin agent can actually do? And so one of the questions is that basal insulin might Eugene E. Wright, Jr., MD: I think in that context that the goal for Edward, given his relatively young age, his lack of comorbidities, his goal and his target would be 7 percent or less. And as you have identified, these other therapies are quite unlikely to get him to that. One of the things about insulin is it is the most effective drug that we have in lowering A1C.

10 Steven V. Edelman, MD: You both said it all quite well. I think basal insulin, it would be nice to know what his fasting blood sugars are. GLP-1 could be also used, but as you mentioned in the beginning, Priscilla, adding it later to basal insulin or vice versa is quite an effective strategy as well. Eugene E. Wright, Jr., MD: Let us talk about the barriers for initiation of insulin in Edward. He has sense of personal failure, and we want to stress with him the separation between his personal behaviors and the progression of type 2 diabetes in this case. His sense of his mother having started insulin prior to having a fatal stroke. We want to try to use our experience in that, in many patients, starting insulin earlier prevents these complications. The issue of hypoglycemia or that he has seen hypoglycemia in others with diabetes at work who take insulin. We need to make sure that he has a good tool kit for one, recognizing and rescuing from that. And that he is confident and comfortable in using these tools. And his concern about insulin injections being permanent and inconvenient. Certainly, we can address the notion that diabetes is a progressive illness, and we have a goal, and that we use all the therapies that we have available to achieve and maintain that goal. And the convenience issue, once people find that starting basal insulin can be done once a day, comfortably, confidently, the convenience issue tends to be less of an issue. Priscilla A. Hollander, MD, PhD: I have seen that a number of patients, after getting started on insulin, often do feel better. They will admit, well, I maybe should have started this earlier. Steven V. Edelman, MD: You are absolutely right. I give them the 30-day challenge. I say if the injections hurt too much or if it just does not work or you just want to stop it, we will. And they love the fact that if it is not working they can stop it. But I agree with you, Priscilla. People do not realize how bad they were feeling, and finally, after fighting off high blood sugars for years with oral agents that are not quite doing it, they feel much better. complications or death. I emphasize that it is often the lack of insulin that causes the complications, in my experience. Priscilla A. Hollander, MD, PhD: And I think also a point to be made that, yes, there are other people who have diabetes and they have certain challenges, but that every person is an individual and perhaps that other people have not had the most optimal instruction in how to deal with their diabetes. Because that concern about what happens in other people is not an uncommon one. Eugene E. Wright, Jr., MD: We think about the pain that may or may not be associated with injections. I like to give them the first shot right there in the office. Either a dry shot or a wet shot depending on where they are at that particular point in time. Once they experience that, a lot of this sense of pain associated with the injection is overcome immediately. Issues about hypoglycemia, I like to arm my patients with a tool kit both for hypo- as well as hyperglycemia so that they can see and start to understand the meanings of these blood sugar checks that they have. And when they see things, to relate it back to behaviors and activities so that they are confident that they can recognize what is going on. Steven V. Edelman, MD: That is why I like to give people a self-titration with their basal so that they can actually test their blood sugar, do something about it, and I am sure all of us do here. Because you just do not see patients frequent enough to do that. Priscilla A. Hollander, MD, PhD: And the emphasis on balance. That you are balancing this insulin and your whole regimen against your activity and against your carbohydrate intake, and trying to make patients very aware of that program. Eugene E. Wright, Jr., MD: And one of the beauties of starting the basal insulin is that they have much more control and they can see the results very quickly. And they are able to say, yes, I can see how this is working. Eugene E. Wright, Jr., MD: You have identified some of the strategies that we talk about to these common barriers. If I need insulin, it is a personal failure. But we have got some strategies for dealing with that. Talking about the progressive nature of the disease. Insulin is not effective. Some strategies for dealing with that using our own experience in how this has worked very well in other patients, and again, how some of the current insulins that we have now more closely mimic what is actually produced in the body. More natural, if you will. And insulin causes Insulin causes weight gain not uncommon that we hear. And again, we talk about the newer agents that we have, we talk about using insulin with other medications that may mitigate that weight gain some. And the sense of independence if they start insulin, that it is somehow restrictive on their lifestyle. We talk about that. And again, looking at the opportunities to take it once a day, using discretion, taking it home. When starting basal insulin, not having to take this during the day.

11 Priscilla A. Hollander, MD, PhD: Getting back to the weight gain, and this is where I think can be a challenge for primary care physicians and patients in understanding that if you are at an A1C of 9 percent, you are eating excess calories that you are not using. And if you do not change your diet as you try to bring your glucose levels into the normal range, you will gain weight. This is a difficult concept. But taking the time to try to stress that with the patient can pay some very large dividends in terms of the weight issue. Eugene E. Wright, Jr., MD: Good point. So let me just summarize this, what we did with Edward. In this case, we sent him to the diabetes educator this time to work on his barriers and how to use insulin. He agreed to start basal insulin once a day at bedtime and agreed that it would not impact his lifestyle too much. We eliminated pioglitazone and glimepiride. A couple of reasons: one, we were concerned about potential hypoglycemia as well as weight and weight-mitigating strategy. His other medications, the SGLT-2 and the metformin, were kept in place, and we instituted a systematic monitoring plan for him so that he could actually see these results. Priscilla A. Hollander, MD, PhD: Excellent case. Steven V. Edelman, MD: Now it is my turn to tell you about one of my patients and how it can relate to using follow-on biologics in clinical practice. Let me tell you about a 61-year-old woman of Chinese descent. Her name is Georgia, she has had type 2 diabetes for seven years, and she was diagnosed on a routine physical exam. Her BMI is 29, she does have a history of coronary artery disease status post 2 stents, and she was treated for three years on diet and exercise alone. And to be quite frank, she was very resistant to taking a prescription medication, and she was more prone to taking herbal supplements from her ethnic background. And she was eventually started on a sulfonylurea. Her A1C was above 10 percent, and cost was an issue for her. And that has been true ever since I have been seeing this woman. Over the next 12 months, her A1C did not quite get to where we wanted, and we added on metformin. We are limited to 500 mg twice a day due to GI side effects, and then eventually a third oral agent was added, a DPP-4 inhibitor. So her A1C came down from 8.9 down to 7. - percent, and then you can see the list of her other medications for her typical metabolic syndrome and coronary artery disease. So here is our audience response question. How would you modify Georgia s antihyperglycemic regimen? A, add basal insulin, B, add pioglitazone, C, add an SGLT-2 inhibitor, or D, stop the DPP-4 and add a GLP-1 receptor agonist? Some thoughts from my colleagues? Eugene E. Wright, Jr., MD: The first question I would have is, what our target goal for Georgia? Given this patient, I think that a goal of 7 or less would be reasonable. The other question that I would ask in that, is she having symptoms of hypoglycemia with a sulfonylurea? I understand that her A1C is still high; however, she is on a sulfonylurea, and they are associated with increased rates of hypoglycemia. Steven V. Edelman, MD: She reports none; however, now that we are using continuous glucose monitors in a lot of these type 2 studies, there is a lot of asymptomatic hypoglycemia. And you are right, with coronary artery disease, you want to avoid hypoglycemia at all costs. Priscilla A. Hollander, MD, PhD: So that might temper your A1C goals slightly. But it does not sound like her heart disease has been that challenging or that she is not functional in that regard. I think at this point, you are right, there are a number of ways to approach this. One would be to discontinue the DPP-4 and add a GLP-1. This has greater efficacy than the DPP-4, and we have seen some weight loss which could be helpful, and might be enough to bring her A1C into the low 7 range. Whether it would drop her below 7, I do not know, but probably down to a 7.1, a 7.2. SGLT-2 inhibitor could be another choice, although in studies it is not quite as effective as is the GLP-1, although you do see some weight loss. And there are different side effects with SGLT-2 inhibitors which we can see at time. Steven V. Edelman, MD: Let me tell you more about the case. So here are some more factors and data on our patient. She is middle in the stage of her disease, talking about the natural history of type 2. So she does not have full endogenous insulin secretion function, so they are somewhere in between. It would be nice to get her A1C close to 7 I think we would agree with that. Avoiding hypoglycemia. Generally, she does not have a big risk for hypoglycemia. She was not reporting any and she does have weight problems. She is not in the obese category, just overweight, but she is hovering there. You can see some of her data. I have told you most of her data. Her fasting blood sugar is 185 on average. And we have talked about her therapy, she is on three oral agents. So let us take a look at her glucose diary. I asked her to test not four times a day but just do some testing. And her