Applying Data to Practice: Where Do Modern Insulins Fit in My Diabetes Practice CME

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1 Applying Data to Practice: Where Do Modern Insulins Fit in My Diabetes Practice CME Supported by an independent educational grant from Novo Nordisk CME Provider: The Endocrine Society

2 Applying Data to Practice: Where Do Modern Insulins Fit in My Diabetes Practice CME This article is a CME certified activity. To earn credit for this activity visit: CME Released: 10/30/2015; Valid for credit through 10/30/2016 Target Audience This activity is intended for diabetologists and endocrinologists, primary care providers, cardiologists, and other healthcare professionals who treat patients with diabetes. Goal Statment The goal of this activity is to improve the care of patients with diabetes who need insulin, focusing on the role and clinical benefits of newer, next-generation basal insulin analogs. Learning Objectives Upon completion of this activity, participants will be able to: 1. Assess safety and efficacy data of novel and emerging basal insulin analogs compared with traditional options, focusing on effect on glycated hemoglobin (HbA 1c ), risk for hypoglycemia, and potential for weight gain 2. Evaluate the potential impact of new data on treatment approaches for patients with type 2 diabetes Credits Available Physicians - maximum of 0.50 AMA PRA Category 1 Credit(s) Accreditation Statements The Endocrine Society is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The Endocrine Society has achieved Accreditation with Commendation. The Endocrine Society designates this enduring material for a maximum of 0.50 AMA PRA Category 1 Credit(s). Physicians should claim only the credit commensurate with the extent of their participation in the activity. Contact This Provider For questions regarding the content of this activity, contact the accreditated provider for this CME/CE activity. Pg.2

3 Instructions for Participation and Credit There are no fees for participating in or receiving credit for this online educational activity. For information on applicability and acceptance of continuing education credit for this activity, please consult your professional licensing board. This activity is designed to be completed within the time designated on the title page; physicians should claim only those credits that reflect the time actually spent in the activity. To successfully earn credit, participants must complete the activity online during the valid credit period that is noted on the title page. To receive AMA PRA Category 1 Credit, you must pass the post-test. Follow these steps to earn CME/CE credit*: 1. Read the target audience, learning objectives, and author disclosures. 2. Study the educational content online or printed out. 3. Online, choose the best answer to each test question. To receive a certificate, you must receive a passing score. We encourage you to complete the Activity Evaluation to provide feedback for future programming. You may now view or print the certificate from your CME/CE Tracker. You may print the certificate but you cannot alter it. Credits will be tallied in your CME/CE Tracker and archived for 6 years; at any point within this time period you can print out the tally as well as the certificates from the CME/CE Tracker. *The credit that you receive is based on your user profile. Hardware/Software Requirements To access activities, users will need: A computer with an Internet connection. Internet Explorer 8.x or higher, the latest versions of Firefox or Safari, or any other W3C standards compliant browser. Adobe Flash Player and/or an HTML5 capable browser may be required for video or audio playback. Occasionally other additional software may be required such as PowerPoint or Adobe Acrobat Reader. Pg.3

4 Applying Data to Practice: Where Do Modern Insulins Fit in My Diabetes Practice CME Authors and Disclosures Author(s) Statement of Independence As a provider of continuing medical education (CME) accredited by the Accreditation Council for Continuing Medical Education, the Endocrine Society has a policy of ensuring that the content and quality of this educational activity are balanced, independent, objective, and scientifically rigorous. The scientific content of this activity was developed under the supervision of the Endocrine Society s Special Programs Committee (SPC). The commercial supporter(s) of this activity have no influence over the planning of this CME activity. Disclosure Policy The faculty, committee members, and staff who are in a position to control the content of this activity are required to disclose to the Endocrine Society and to learners any relevant financial relationship(s) of the individual or spouse/partner that have occurred within the last 12 months with any commercial interest(s) whose products or services are related to the CME content. Financial relationships are defined by remuneration in any amount from the commercial interest(s) in the form of grants; research support; consulting fees; salary; ownership interest (eg, stocks, stock options, or ownership interest excluding diversified mutual funds); honoraria or other payments for participation in speakers bureaus, advisory boards, or boards of directors; or other financial benefits. The intent of this disclosure is not to prevent CME planners with relevant financial relationships from planning or delivery of content, but rather to provide learners with information that allows them to make their own judgments of whether these financial relationships may have influenced the educational activity with regard to exposition or conclusion. The Endocrine Society has reviewed all disclosures and resolved or managed all identified conflicts of interest, as applicable. Policy on Unlabeled/Off-Label Use The Endocrine Society has determined that disclosure of unlabeled/off-label or investigational use of commercial product(s) is informative for audiences and therefore requires this information to be disclosed to the learners at the beginning of the presentation. Uses of specific therapeutic agents, devices, and other products discussed in this educational activity may not be the same as those indicated in product labeling approved by the Food and Drug Administration (FDA). The Endocrine Society requires that any discussions of such off-label use be based on scientific research that conforms to generally accepted standards of experimental design, data collection, and data analysis. Before recommending or prescribing any therapeutic agent or device, learners should review the complete prescribing information, including indications, contraindications, warnings, precautions, and adverse events. Moderator John (Jack) L. Leahy, MD Professor of Medicine; Co-Chief, Division of Endocrinology, Diabetes, and Metabolism, University of Vermont, Burlington, Vermont Disclosure: John (Jack) L. Leahy, MD, has disclosed the following relevant financial relationships: Served as an advisor or consultant for: Janssen Pharmaceuticals, Inc.; Merck & Co., Inc.; Novo Nordisk; Sanofi Dr Leahy does not intend to discuss off-label uses of drugs, mechanical devices, biologics, or diagnostics approved by the FDA for use in the United States. Dr Leahy does intend to discuss investigational drugs, mechanical devices, biologics, or diagnostics not approved by the FDA for use in the United States. Panelists Lawrence Blonde, MD Director, Ochsner Diabetes Clinical Research Unit, Frank Riddick Diabetes Institute, Department of Endocrinology, Ochsner Medical Center, New Orleans, Louisiana Pg.4

5 Disclosure: Lawrence Blonde, MD, has disclosed the following relevant financial relationships: Served as an advisor or consultant for: AstraZeneca Pharmaceuticals LP; GlaxoSmithKline; Intarcia Therapeutics, Inc.; Janssen Pharmaceuticals, Inc.; Merck & Co., Inc.; Novo Nordisk; Quest Diagnostics; Sanofi Served as a speaker or a member of a speakers bureau for: AstraZeneca Pharmaceuticals LP; Janssen Pharmaceuticals, Inc.; Merck & Co., Inc.; Novo Nordisk; Sanofi Received grants for clinical research from: Lexicon Pharmaceuticals, Inc.; Lilly; Novo Nordisk; Sanofi Dr Blonde does not intend to discuss off-label uses of drugs, mechanical devices, biologics, or diagnostics approved by the FDA for use in the United States. Dr Blonde does intend to discuss investigational drugs, mechanical devices, biologics, or diagnostics not approved by the FDA for use in the United States. Melanie J. Davies, MB, ChB, MD, FRCP, FRCGP Professor of Diabetes Medicine, University of Leicester; Honorary Consultant, University Hospitals of Leicester, Leicester, Leicestershire, United Kingdom Disclosure: Melanie J. Davies, MB, ChB, MD, FRCP, FRCGP, has disclosed the following relevant financial relationships: Served as an advisor or consultant for: AstraZeneca Pharmaceuticals, LP; Boehringer Ingelheim Pharmaceuticals, Inc.; Lilly; Janssen Pharmaceuticals, Inc.; Merck Sharp & Dohme Corp.; Novo Nordisk; Sanofi Served as a speaker or a member of a speakers bureau for: AstraZeneca Pharmaceuticals, LP; Boehringer Ingelheim Pharmaceuticals, Inc.; Lilly; Janssen Pharmaceuticals, Inc.; Merck Sharp & Dohme Corp.; Mitsubishi Tanabe Pharma Corporation; Novo Nordisk; Sanofi Received grants for clinical research from: Lilly; Novo Nordisk; Sanofi Dr Davies does not intend to discuss off-label uses of drugs, mechanical devices, biologics, or diagnostics approved by the FDA for use in the United States. Dr Davies does intend to discuss investigational drugs, mechanical devices, biologics, or diagnostics not approved by the FDA for use in the United States. Editor(s) Anne G. Le, PharmD, RPh Senior Scientific Director, Medscape, LLC Disclosure: Anne G. Le, PharmD, RPh, has disclosed no relevant financial relationships. CME Reviewer/Nurse Planner (If applicable) Amy Bernard, MS, BSN, RN-BC Lead Nurse Planner, Medscape, LLC Disclosure: Amy Bernard, MS, BSN, RN-BC, has disclosed no relevant financial relationships. CME Accreditation Committee and Peer Reviewer Guillermo Umpierrez, MD, CDE Professor of Medicine; Director, Grady Hospital Research Unit, A-CTSI, Emory University School of Medicine; Section Head, Diabetes & Endocrinology, Grady Health System, Atlanta, Georgia Disclosure: Guillermo Umpierrez, MD, CDE, has disclosed the following relevant financial relationships: Served as an advisor or consultant for: Abbott Laboratories; Boehringer Ingelheim Pharmaceuticals, Inc.; Merck & Co., Inc.; Novo Nordisk; Regeneron Pharmaceuticals, Inc.; Sanofi Received grants for clinical research from: Boehringer Ingelheim Pharmaceuticals, Inc.; Merck & Co., Inc.; Novo Nordisk, Regeneron Pharmaceuticals, Inc. Pg.5

6 Applying Data to Practice: Where Do Modern Insulins Fit in My Diabetes Practice CME Jack L. Leahy, MD: Hello. I am Dr Jack Leahy, Professor, Department of Medicine, and Co-Director of the Division of Endocrinology, Diabetes, and Metabolism at the University of Vermont, College of Medicine in the United States. Welcome to this program on modern insulins for the treatment of diabetes, which is being developed in collaboration with the Endocrine Society. Pg.6

7 Joining me today is Dr Lawrence Blonde. Larry is the Director of the Ochsner Diabetes Clinical Research Unit at the Frank Riddick Diabetes Institute at the Ochsner Medical Center in New Orleans, Louisiana. Larry, welcome. Lawrence Blonde, MD: Pleasure to be here, Jack. Dr Leahy: Dr Melanie Davies. Melanie is a Professor of Diabetes Medicine at the University of Leicester and Honorary Consultant at the University Hospitals of Leicester, in Leicestershire, the United Kingdom. Melanie, welcome. Melanie J. Davies, MB, ChB, MD, FRCP, FRCGP: Hi, Jack. Pg.7

8 Applying Data to Practice: Where Do Modern Insulins Fit in My Diabetes Practice CME Dr Leahy: I would like to mention that this program will include a discussion of investigational agents that are not approved by the Food and Drug Administration (FDA) for use in the United States. In addition, we will be discussing data that were presented at the 51st Annual Meeting of the European Association for the Study of Diabetes (EASD) in Stockholm, Sweden, in These data should be considered preliminary until published in a peer-review journal. The goals of today s program are to assess the safety and efficacy data of novel and emerging basal insulin analogs compared with traditional options focusing on the effect on glycated hemoglobin (HbA 1c ), the risk for hypoglycemia, and potential for weight gain; and to evaluate the potential impact of new data on treatment approaches for patients with type 2 diabetes. Pg.8

9 Role of Basal Insulin in the Treatment of Diabetes I want to discuss with you, Larry, a really important question that clinicians want to know and that is when should they start thinking about injectable medications in type 2 diabetes? Dr Blonde: When oral medications do not allow people to get to glycemic target one needs to consider injectable agents. On the other hand, for some patients with type 2 diabetes, even at the time of diagnosis they might have such poor glycemic control and be so symptomatic that by initially treating with insulin they may be able to rapidly lower glucose, reduce glucose toxicity. Over time the insulin can often be down titrated, maybe even discontinued and treatment with non-insulin agents may be possible. Therefore, some type 2 patients may benefit from initial insulin therapy. [1] For everyone else, patients usually get started on oral agents and -- usually when 2 medications or 3 medications do not get people to goal -- one starts to think about injectable agents. Pg.9

10 Applying Data to Practice: Where Do Modern Insulins Fit in My Diabetes Practice CME Over the last several years, we have had glucagon-like peptide-1 (GLP-1) receptor agonists. There are a number of studies that suggest for patients with HbA 1c between 8% and 8.5% on 1 oral agent that a GLP-1 receptor agonist may be at least as effective as initiating basal insulin for most of those patients and is usually associated with less hypoglycemia and a potential reduction in weight, compared to weight gain with insulin. [2,3] For that reason, one really might consider the GLP-1 receptor agonist to be the first injectable agent in many if not most type 2 diabetes patients. That being said, there are many patients with type 2 diabetes who are being treated with insulin, usually basal insulin, who are still are not under adequate control and one can certainly add a GLP-1 receptor agonist to a basal insulin regimen in such patients and get benefits as well, and may even obviate the need for prandial insulin in a type 2 diabetes patient. Dr Leahy: I think it continues to be a complicated clinical issue: choose basal insulin or choose a GLP-1 agonist. You have advantages and disadvantages to both. Pg.10

11 Dr Blonde: Although there is 1 study in which patients not at goal on metformin all got the GLP-1 receptor agonist liraglutide and 60% of those people got to an HbA 1c < 7% in only 12 weeks. [4] There was a mean loss of weight of approximately 4 kg. Patients who did not get to HbA 1c goal were randomized to either remain on metformin + liraglutide or to have added a basal insulin analog. When they did that, people did not regain the weight that they had lost and they had a pretty low incidence of hypoglycemia, suggesting that when you start with the GLP-1 receptor agonist, if you eventually need insulin you may be less likely to gain as much weight or to have as much hypoglycemia. That may be because you need less insulin. Dr Leahy: We are still focused on basal insulins here and especially new basal insulins that I think are bringing significant advantages. Pg.11

12 Applying Data to Practice: Where Do Modern Insulins Fit in My Diabetes Practice CME We have in the United States glargine U-300. Please tell us about that agent. Dr Blonde: It is a product with a higher concentration of glargine, a longer duration of action than U-100 glargine, which in some type 2 patients does not last a full 24 hours and has less variability in terms of plasma insulin exposure. [5] That itself is probably an underappreciated important issue, and some studies, including one that we participated in a few years ago where everybody was on insulin, showed that patients who had [less] variability by continuous glucose monitoring system could sense that they had better treatment satisfaction, better perceived health, and better quality of life. [6] Patients, even without hypoglycemia, can sense if their blood triggers are bouncing up and down. So having a basal insulin with less variability may be clinically important. The U-300 has a similar safety and efficacy profile as glargine U-100 but is associated with less weight gain and a lower incidence of hypoglycemic events. [7-9] In a meta-analysis of multiple studies, there was a decrease in severe hypoglycemia with U-300 vs U-100 at night and at any time during 24 hours. [5] Dr Leahy: So a longer duration of action, flatter profile, and less hypoglycemia is the theme with this. Dr Blonde: And similar efficacy. Pg.12

13 Dr Davies: Melanie, I want to go on to you. You have in Europe another new basal long-acting insulin that is called degludec. What can you tell us about that? Dr Davies: We have had degludec available for a couple of years now. This is an insulin attached by glutamic acid spacers to a fatty acid so it results in a larger molecular size, forming multi-hexamers when it is injected. That is the way it prolongs its action. It has a half-life of around 25 hours. It has, again, as you would expect with a flatter longer duration insulin, a lower risk of nocturnal hypoglycemia. It has improved variability and there have also been studies showing you can be flexible with the timing of injection, which is obviously convenient for patients. [10,11] It is available as a U-100 and a U-200 insulin, so in those type 2 patients who require high doses that is an advantage as well because you can give a higher dose at a lower volume. There have been studies in type 1 and type 2 patients again showing consistent lower rates of nocturnal hypoglycemia and equivalent HbA 1c reductions compared with insulin glargine. [12,13] Pg.13

14 Applying Data to Practice: Where Do Modern Insulins Fit in My Diabetes Practice CME Dr Leahy: You said something really interesting. You said flexible timing, and we actually have clinical data to support that. What does that mean and what is the clinical relevance? Dr Davies: I think for some patients convenience and timing of injection is really important. They did some studies where they forced people to be flexible so they reduced the injection period down to 8 hours or up to 40 hours and there was no difference in terms of the performance of the insulin. [12] This allows patients to be a bit more flexible with the timing. Of course, we do not want to encourage people to be nonadherent but it does, if you are having to rely on a caregiver to give your insulin, allow some flexibility with the timing of the injection. Dr Leahy: It comes up all the time. I work in a university and I take care of college students who have morning classes some days and sleep until 1 o clock in the afternoon on the weekends, and flexible timing, actually, is a very practically important issue. Pg.14

15 Melanie, there is another long-acting basal insulin that is not yet available for use but certainly we have talked a lot about it, pegylated lispro, also called basal insulin lispro.* Tell me about that. Dr Davies: We have much new data about peglispro presented at the European Association for the Study of Diabetes (EASD). [14-19] Pegylated lispro is basically insulin lispro, which is covalently bound to polyethylene glycol (PEG), and it is a very large molecule. It has a large hydrodynamic size, about the same size as albumin and that large size protracts its action, so it has a half-life of around 35 hours. There are about 6 or 7 studies presented at EASD which show that in patients with type 1 and type 2 diabetes there were low rates of nocturnal hypoglycemia, which is an advantage even though these were treat-to-target studies and a number of them were double blind. There was a superior HbA 1c reduction, which seems to be fairly consistent across the studies, and a small weight advantage in the type 2 patients. Pg.15

16 Applying Data to Practice: Where Do Modern Insulins Fit in My Diabetes Practice CME The mechanism of action is that it is more preferential to the liver, [20,21] so there has been in some of the studies an increase in alanine aminotransferase (ALT) and some suggestion of increase in liver fats, particularly if patients have already been on insulin and switched to a pill. That is not the case in the study that I was involved in with insulin-naive type 2 patients, there was no increase in liver fat, but there was a reduction with insulin glargine. [22] Dr Leahy: That is really interesting. When you talked about the liver you focused on the potential downside, which is a bump in transaminases in a few patients and maybe some liver fat; we are still learning. I think perhaps as a profession, as a specialty, we may want a liver-specific insulin; there could be an upside to the liver specificity. Why is that? Dr Davies: I think that is right. All of these 7 studies showed superior HbA 1c with BIL, which is quite a new finding, so to see that happen so consistently with a basal insulin is exciting. We certainly see improvements in variability and some hepato-preferential actions that may be an advantage, [21] so all of this may translate into practical benefits for patients. We need to be clear and understand what is going on in the liver to be sure about that. Dr Leahy: The way I understand it is if you have an insulin that is more focused on working well initially on the liver you can suppress hepatic glucose production and require less insulin to get out into the systemic space which could promote hypoglycemia. That is the theory. We will see if that is true. Dr Davies: Yes. It mimics more of the physiologic action of insulin. Dr Leahy: Absolutely. I think we need to emphasize this because it is amazing. They are doing studies and seeing superiority of peglispro vs glargine U-100. We do not have many head-to-head insulin trials where you see a superiority. Is this actually something important and novel? Dr Davies: I think it is. I think all of these studies were designed to be treat-to-target so they were designed to achieve the same HbA 1c. Three were quite large studies: one in patients with type 1 diabetes and two in type 2 patients. They were all double-blind trials. Consistently across all the studies, you got to a lower HbA 1c. [14-19] Whether that is because of improved variability or less nocturnal hypoglycemia -- I think there are a number of potential mechanisms of action, but it is certainly a consistent finding, which I do not think we can explain yet. Dr Leahy: It is also very confusing for people who are used to lispro as a rapid-acting insulin to initially hear about the new insulin. Now someone comes in and says we have a different lispro. It is attached by pegylation -- what does that do in theory? Pg.16

17 Dr Davies: I think it is centered around the size of the molecule. You stick a great big PEG onto the lispro and it makes it by definition more hepato-selective because the large molecule can get through the fenestrate and the sinusoids into the liver but it cannot penetrate the endothelial barrier in the periphery. It is really sort of a structural way that the insulin is more hepato-selective. Dr Leahy: The other thing about degludec that has people really interested is this combination idea where you can actually have degludec along with the GLP-1 agonist liraglutide and that coformulation is currently under investigation. Tell me about that -- what we know and why that might actually be an interesting coformulation. Dr Davies: We started by talking about how to move to the first injectable and I think we know the advantages of insulin. Insulin is very effective at glucose lowering but you get the risk of hypoglycemia. Often type 2 patients end up on high doses of insulin. We know the advantages of GLP-1 agonists, so combining the 2 makes sense. Essentially, the idea is you parallel titrate up the insulin with the GLP-1 agonist. Certainly in the DUAL studies, which are the insulin degludec/liraglutide (IDegLira) studies, some of which are being presented here at EASD, you get excellent HbA 1c reduction, low rates of hypoglycemia, an insulin-sparing effect, and also importantly you get very low rates of gastrointestinal (GI) adverse effects with the GLP-1 agonist because of this very slow titration up. [23-26] Dr Leahy: The clinical trials with the combinations, both that you mentioned, are stunning in terms of obtained HbA 1c and weight protection. Larry, what is your read of the idea of a combination GLP-1 agonist and insulin? Pg.17

18 Applying Data to Practice: Where Do Modern Insulins Fit in My Diabetes Practice CME Dr Blonde: I agree with you. The results have really been stunning, with HbA 1c levels in the mid 6s accomplished in these trials. I think that for type 2 patients where they are definitely going to need insulin, this is a better way of starting basal insulin and easier for many patients and clinicians. I think, although we do not have the data, it may reduce the need subsequently for any prandial insulin. I think it is very interesting. What I am not sure of, for patients we described earlier where there is a possibility you may get them to goal with a GLP-1 receptor agonist plus oral medications without insulin, would it be better to start with that and then go to insulin if you need to? Those studies have not been done, but certainly for patients where it is almost for sure they are going to need insulin this is a better way of starting a basal insulin. Dr Leahy: I loved how you described it. We are having enormous conversations here in the United States about the theory, because we do not have this agent yet, and really trying to decide, when we get coformulations, where are they going to fit? What have you learned in the United Kingdom? Dr Davies: There has been a big debate about where this agent fits; we have been using IDegLira in Europe. I suppose there are 2 obvious areas. One is using it as the first injectable and there are a cohort of patients where weight is an issue, the HbA 1c is relatively high, so you know that if you use insulin you are going to use pretty big doses and you might not get to target with the GLP-1 agonist alone. There is certainly a group of patients in whom this would be the preferred first injectable. The second group comprise those people already established on basal insulin in which you want to intensify; in this instance, it would be a fairly simple regimen for the patient because it is 1 injection and a slow titration. In these patients, or even in some patients who have been on a GLP-1 agonist and have not quite reached their target HbA 1c, you can switch them to the combination. Dr Leahy: I think it is important the way you described it because there are many different patients for whom I can imagine going to that coformulation. Also, for me, I think the really important issue is that many primary care providers still struggle past basal insulin. They are not exactly sure what to do. In many ways this would be an agent similar to what they are used to. You start with 1 injection, you titrate it like basal insulin, and to me it is just a better basal insulin. It might make them more effective at trying to control patients as their first injectable. We are going to have to see. Dr Davies: I think it is great for patients because they can get to target quite quickly, it is very convenient, and also because you are reducing the risk of GI intolerability and hypoglycemia, that is a real advantage. Pg.18

19 Clinical Application of New Data Dr Leahy: I want to move on and talk about a few of the things we have heard about so far. The message I have taken home from the new basal insulins that are either available for use or in clinical development is a longer duration of action, a flatter profile, less hypoglycemia, and maybe targeting HbA 1c. That is a little difficult because it varies from drug to drug. Larry, I want to start with U-300 because we do have that in the United States. We have heard many positives. There are some surprising observations. One is the insulin dose seems to be higher vs U-100. Why is that? Dr Blonde: It may be because of the greater concentration leading to a longer residence time in the subcutaneous tissue, that there could be more time for some metabolism of the U-300 in the subcutaneous tissue resulting in a somewhat higher dose. The amount is going to be variable patient-to-patient and generally not more than a 10% higher dose. Dr Leahy: If we say that, what then are the prescribing recommendations? Maybe Europe is exactly the same, but if we take someone off U-100 to go to U-300, how do we do the transformation? Dr Blonde: I think in general one usually starts with an equivalent dose but is prepared to titrate up. [9] Again, it is not a huge difference that has been seen. Dr Leahy: That is not the same with degludec, is it? The dosing seems to be pretty equivalent? Dr Davies: Yes. The dosing seems to be reasonably equivalent and interestingly with peglispro you see about a 10% increase in the dose in the type 2 studies compared with insulin glargine. Again, with that, there is a small increase in the doses required. Dr Leahy: We talked about the advantage of flexibility in dosing and again I really believe that is true. It is helpful for our patients. Dr Blonde: Not only for patients but also for clinicians. There are any number of times clinicians are called by patients who say they are now at work and forgot to take their insulin. Clinicians wonder what they should do about this. Pg.19

20 Applying Data to Practice: Where Do Modern Insulins Fit in My Diabetes Practice CME Dr Leahy: Good, but there is a downside to a longer insulin and I think we have to relearn a little bit how we think about titration of insulin. I happen to be a weird guy. I titrate every day 1 U, which is none of the official recommendation but I am not going to be able to do that with these longer insulins. Why is that? Dr Blonde: Because of the longer half-life it is recommended to titrate about every 3 days with the U-300 [9] and with degludec, [once-weekly]. [27] Dr Davies: With BIL or peglispro it was pretty much the modified treat-to-target regimen so titrate once or twice a week. [18] I think it is pretty difficult every day but I think every 3 days or twice a week as we have done with some of the other treat-to-target algorithms is perfectly reasonable and that has been used in many of the studies. Pg.20

21 Dr Leahy: Melanie, I want to ask you a difficult question. We have spent 10 to 15 years telling our primary care providers that the analog insulins are such an improvement over our traditional human insulins and they came with so many advantages. I think we are all pretty comfortable, including most primary care providers, with the current basal insulins. Now we come along and we say longer duration of action, less flexibility, less hypoglycemia with these next-generation basal insulin analogs, when we sort of told them for the longest time what we had was pretty good. Who should get the new basal insulins, and where do they really fit? What is your thought on that? Dr Davies: I think you are right. Every time we make an improvement, we are fine-tuning what we currently have. You are right. I think that detemir and glargine are very good insulins and you can do very well with them. But if you look at the data, there is still much clinical inertia, there still is hypoglycemia that limits patients getting to target. There is still a fear of hypoglycemia, and I think there are particular groups, including elderly patients and some of our younger type 2 patients who are struggling to get to target, where these innovations and new combinations may be of real benefit. Dr Leahy: Larry, what do you think? Pg.21

22 Applying Data to Practice: Where Do Modern Insulins Fit in My Diabetes Practice CME Dr Blonde: I agree. Last year at the American Diabetes Association (ADA) and again at EASD we presented some data where we looked at some trials with a standard conventional basal insulin analog. [28] In the regulatory, randomized control trials, only about half the people actually got to an HbA 1c <7%. About 80% of people either got to an HbA 1c <7% or they achieved a fasting glucose of at least <130 mg/dl, indicating that they got adequate titration (of the basal insulin), so even in a randomized clinical trial many people did not get to goal. In this same study, we also looked at data from the GE Centricity database from actual practice electronic medical records, and there, only about 25% of people got to goal HbA 1c. Less than half the people either got to an HbA 1c <7% and/or a fasting plasma glucose (FPG) <130 mg/dl, indicating that in actual practice there is an issue in terms of titrating the basal insulin. It may be these newer insulins with less hypoglycemia and a flatter profile may allow more people to get to goal. Dr Leahy: I think some of the things we talk about now may be a little invisible to providers. The average provider thinks the rate of hypoglycemia with the current basal insulins is pretty small. I am guessing it is not quite as small as they think, certainly in patients who are on sulfonylureas. That actually may be an important advantage but we need some more time to know that. Dr Blonde: We also need more studies about the impact of nonsevere hypoglycemia which many people think is minor, but it is not minor to patients. Dr Leahy: That is all the positives. Melanie, are there any negatives? Who would we worry about with 1 of these long-acting insulins? Pg.22

23 Dr Davies: I suppose the advantage of U-300 in some ways is they have done the ORIGIN study, we have good long-term safety data with insulin glargine. [29] I think that is fairly clear now. I think with all of the new therapies we need to see how things are going to play out in terms of safety. I think BIL has some excellent properties where we just need to understand what is going on in the liver. I think with degludec, certainly in Europe, we are very reassured. I think with all of these things it is also about the cost as well. We need to have more accessible treatments, but because of cost we may need to use these agents in patients who are likely to benefit most and those at the highest risk of hypoglycemia. Dr Leahy: Do you have any prescribing guidelines related to renal function related to age with degludec? Dr Davies: My understanding with degludec is you can use it across the spectrum down to moderate renal impairment. They have not done studies in patients with severe renal impairment but there is no reason to think we could not use it in terms of the way the insulin is metabolized and excreted. Pg.23

24 Applying Data to Practice: Where Do Modern Insulins Fit in My Diabetes Practice CME Dr Leahy: One last question. It actually comes up all the time from people who are confused. If we have insulins now that work 36 hours, maybe even a touch longer depending upon the patient, do we inject it every day? Why do we do it every day? Dr Davies: There were studies when you did it every 3 days and they did not go well, so the glycemic control tended to deteriorate. I think from an adherence point of view, taking the agent every other day or every third day is probably a little confusing as well. We certainly need to take them every day, but the issue is if you forget it is not such a disaster as it is with the current basal insulins. Dr Leahy: I think that is incredibly important because that is real life. Something gets ruined and next thing you know you are 8 hours past your insulin injection. Any last comments, Larry? Dr Blonde: I think that the titration every 3 days or twice a week is not going to be a big deal for many patients, particularly because so many people now have smartphones. It is easy to program that in to remind people. Dr Leahy: Melanie, any last comments about any of this? Dr Davies: No. I think it is exciting times though. We have never had so much choice in terms of insulin therapy. Dr Leahy: Exciting but a little complicating, I think. Larry, Melanie, I would like to thank you both for joining me in this interesting discussion. I really enjoyed it. I think it has been really done great. Pg.24

25 Close I want to thank you all for participating in this activity. Please click on the Earn CME Credit link to revisit the questions presented at the beginning of this activity and see what you have learned. The CME posttest and evaluation will follow. Thank you very much. Pg.25