A Discussion About the 2012 ADA/EASD Position Statement

Dr. Doron Schneider and Dr. Jack Leahy discuss  the 2012 ADA/EASD position statement on management of type 2 diabetes and its implications to clinical care.

Dr. Doron Schneider: Hi, I'm Dr. Doron Schneider. I'm a general internist at Abington Health Center right outside of Philadelphia. There I am the chief quality and safety officer for the health system and deputy program director for internal medicine. And with me I have Dr. Jack Leahy. Jack …
Dr. Jack Leahy: Great. I'm Jack Leahy. I'm the endocrine chief at the University of Vermont here in Burlington. I'm very interested in diabetes pathogenesis, but also clinical care.
Dr. Doron Schneider: Thanks, Jack, and so we are hoping in the next period of time to provide some reflections on what is occurring in diabetes care, especially in light of the new guidelines that are out from the ADA/EASD, and really fit them into the evolving landscape of diabetes care. With healthcare reform, Affordable Care Act, the landscape is rapidly shifting, and this is an attempt on our part to really provide some reflections about that. So diabetes, as we all know, is a disease of scale. There are over 25 million people in the United States, about 8 percent of the population has diabetes, and it is growing in its prevalence and incidence. It's a condition that overwhelms the ability for the endocrinologist community alone to care for so it requires primary care doctors to really be facile with being able to manage both the chronic nature of it and then the acute event that occurs when it's not appropriately managed. As we know diabetes involves every organ system -- from the heart, the liver, the kidneys, eyes, nerves, etc. and because of that -- and because it also runs in sort of a gang of other conditions, including high cholesterol, high blood pressure -- it's not uncommon for folks with diabetes to require numerous medications -- two, three, even four diabetes medications and as many as ten or more medications in all --to control these chronic conditions. And is increasingly becoming more complicated as more and more drugs are coming on the market -- for example, flozins are going to shortly be arriving, these SGL2 active medications, for example, will increasingly further complicate the landscape for how to provide excellent glycemic control for patients. Also, on the landscape within the last several years: new studies which really are out now from ACCORD, ADVANCE AND VA diabetes trials, which allow for there to be more understanding about the benefits and risks of glycemic control. Now it really does require these primary care doctor to understand the nuances of those trials. So we've added sort of the backdrop -- medically we now have these ADA/EASD guidelines that help us provide an overview that is very much patient centered to the primary care community and to the endocrine community and we thought that we'd have Jack sort of walk through a summary of those guidelines, the philosophy of why they are positioned as such and then we'll get into the details of those guidelines. So with that queued up, Jack you want to walk us through those guidelines?
Dr. Jack Leahy: Great, Doron, thank you very much. The introduction is right on target. So we have this new set of guidelines. It's actually interesting you used that term because I'm not sure that's exactly the term I would use, and hopefully, my few comments will explain why this is. You know, this all started a few years ago when the ADA (obviously, the American organization) got together with the European counterpart, the EASD, and created what were called consensus statements, which actually were not done by the organizations, but were really just getting a group of people together who put these recommendations together and it was really their recommendations. And if you go back and look at those they're interesting because they very much try and give specific instructions of what to do. They're not totally built that way, but they certainly provide information about --[for example] you start with a certain drug; you can go to another drug; there [are] a lot of drugs out there but probably some are better than another, [etc.]. They sort of gave their thought processes as to how they balanced out why they would chose one drug over another and very much focused on the need to meet a goal and the goal was pretty uniform which was get that A1C less than 7 percent and try and do it for every patient. So there are two of those. The second one was more or less an evolution to include some of the newer therapies versus the first one. These new guidelines, which came out online a couple of months ago -- they're in print very soon -- you know they're called a “position statement” from the ADAD/EASD, a very different term versus the consensus statement from the prior two and the position statement really is not specific instructions. It's more or less a discussion of the marketplace -- more or less a discussion of really the different agents that are out there and also tries to build in a philosophy as to how providers should approach this. And probably the dominant thing you see, I mean, the first thing you read is exactly what you said, is this concept of patient-centric care and also individualization of care. This idea that an A1C of 7 is right for everybody is really gone and now it's focused on "identify what is the appropriate target goal" (one of them should be A1C, but also things like safety and weight control and these kind of things), should be done in concert with a clear discussion with the patient so the patient understands the pros and cons and helps make the decision as to specific therapy. That's all based upon the idea that the patient, one, it's [the patient’s] illness, but also it's based on the idea that compliance and enthusiasm and satisfaction in all these different concepts (that should impact the quality of care) will be determined by the patient and his decisions are being made around the things that are most important to [him]. So that's the core starting point and a lot of discussion is related to that. And then it moves into specific recommendations of the kinds of therapies that are out there and how they might be used. And if you go read that document it's important to look at the figures. The figures are important to me because they often show up in teaching sessions. And if you go to the figure that really lays out the sequence of potential therapy, I think one can describe what this document says pretty quickly. There's general agreement that the appropriate starting drug in Type 2 diabetes for most patients is metformin. They understand that there are some contraindications, and there are also some intolerance the patients have, but as a general statement in most populations around the world it's a good starting drug. And then after that essentially what they say is, you know, you have a lot of choices, and there's really not any proven literature that supports that one choice is necessarily superior to the other. Again, it sort of depends upon what the sequences of things that you and the patient discuss and decide are most important for them. So it certainly is controlled, but it could be weight issues, it could be safety, it could be hypoglycemia, it could be cost. [There are] a lot of things to think about. So in the second tier they say you can do sulfonylurea, you can do an insulin sensitizer, you can do the incretin therapies -- the orals, the DPP-IVs or the injected, the GLP-1 drugs. They say you can do basal insulin and essentially they provide a lot of information about those therapies and provide some minimal guidance as to what pathway you might go down. And then it continues because they say if that doesn't work to get to the goals you've set out then you can move to a third line of therapy that could be a third non-insulin agent and all the things I just mentioned could be mixed and matched and be added. And then if that doesn't work you can move on to the sort of final line of therapy and that would be insulin. And so it's very much a discussion of options and what you might think about and much less a discussion of  "here's a prescribed sequence with a limited number of choices -- you should really follow this prescribed sequence". And then finally it ends up with a couple page discussion of special situations. What do you with people with bad livers, with bad kidneys, older folks, other kinds of issues and just as a general comment for me, I actually like that part of the guidelines quite a bit. I think it's useful. They have a section on insulin usage. Less prescriptive than the prior consensus statements, where those consensus statements talk a lot about specific starting dose, talked about adjustment algorithms the patients can do at home, were a little more dictatorial in terms of how you might actually do insulin therapy. This one is a little bit less of that, but it does make one statement that I think is timely and useful. It really says that if you're failing your non-insulin therapy then when you move onto the insulin probably the preferred way in most situations is to start a basal insulin -- you have choices -- and then if the basal insulin is not sufficient you can decide if you want to do premixed or if you want to do basal bolus or if you want to do a limited step adding prealbumin, you have some choices. But it tries to deal with this controversy of basal versus premixed and it says probably starting with basal is their preferred choice.
Dr. Doron Schneider: So, Jack, it sounds like there is clarity first off in that this is, in fact, a position statement. That was the first thing that you said --"this not a guideline" -- and really this is a patient-centered approach and from what you are describing there are some features of this position statement that you really like and you just outlined those. Are there features of the guideline -- or this position statement -- that is worrisome to you in any way? Any reflections based on your knowledge of diabetes or your experience taking care of patients that you think you may take issue with or that you would like to clarify? Any aspects of these guidelines or position statement that you think doesn't hit the mark for you?
Dr. Jack Leahy: Well, this is a very important question for me. I have gone on record, I've gone on print, I'm not really in love with these guidelines and I continue to think about that and I think in some respects my belief on that has softened. But, let me go back and tell you exactly kind of where I'm coming from. I've traveled quite a bit internationally and what I see is that the prior ADA/EASD consensus statements, and the figures that were embedded in them, were used internationally for a lot of discussion by doctor groups on how they should be trying to improve diabetes care in their own countries. They were sort of this starting kind of feeling that if the best countries in the world -- the European countries and America -- this is what they're doing clinically, than this is how we should try and evolve our healthcare system in our own countries. And so the prescriptive sort of, dothis, do it this way, thinking about the semi-limited use of drugs worked and at least it had discussion going and they were very good sort of teaching tools to use in teaching sessions with primary care doctors about, you know, here's what this figure shows, here's a reasonable treatment algorithm to think about. It's not perfect. It doesn't include all drugs, but at least it's a starting place to have thoughts. The current position statement was never intended to do that, and, in fact, I'm more aware of that now. I wrote a blog about a month ago that sort of expressed my caution about what I liked, what I didn't like. Since that time I've had a chance to sit down with five of the authors of the position statement -- a couple of Europeans and a couple of Americans -- in different settings. And what came through in that discussion was interesting to me. One of them in particular said to me that they felt it would have been intellectually dishonest if they had tried to be prescriptive within these guidelines because there are really not proven studies out there that say from an efficacy or even an overall therapy point of view, that one agent is absolutely right and one agent is absolutely wrong. And so the position statement reflects [that] there are choices and that those choices have different aspects to them and they need to be thought about and balanced and discussed with the patient. And I think I am more accepting of that. But still having said that, my cautions with these sort of new recommendations are the concept they're really not prescriptive guidelines. So what it means is that our prescribing community -- primary care doctors and specialists -- are going to need to reach a level of expertise and knowledge in this disease that they can really follow these guidelines; which is essentially to go into the room when they see a patient and to go in with enough working knowledge of all the agents that are out there (and all the minuses and pluses) [and] that they can have the correct conversation with the patient and help them be knowledgeable enough to make the decision that is the best decision for them. And so that's my big issue. That I think that's where we need to get to. Beyond that it's a very well-written document. You know, I give it to my medical students, I give it to new house staff when they come onto our service. I think it includes an enormous amount of useful information. And I guess built into all these sort of thoughts that, I have that the general caution would be, one, that if it's not overly prescriptive we need to know that. But secondly, it worries me and I worry a lot about the concept of just people [getting] stuck and not advancing therapy. Because at least in the prior guidelines, or the prior consensus statements, there was a real push [that] if drug A doesn't work, go to drug B or if drug B doesn't work go to drug C. And for instance, if you go back to those original consensus statements they were the beginning of statements that when someone is initially diagnosed with Type 2 diabetes they should be placed on metformin right away irrespective of what the hemoglobin A1C value was and used in concert with lifestyle improvement, not wait to see if lifestyle improvement works and then add metformin if it doesn't. And the whole statement buried within those documents was the concept that, you know, lifestyle alone just rarely works over the long term for people. We shouldn't wait. We shouldn't sort of be stuck in not advancing therapy, so let's start therapy, i.e., metformin. So that's sort of my issue with the new one. Again, it is with discussions with patients with making decisions with what to do, what sort of first choice of how to do a drug, what we do with that. It might allow this sort of concept of just waiting and being slower to make treatment advances than really we should do because if the conversation with the patient is, you know, " if your A1C is not where it needs to be, we've tried a drug or two and it's not there, we need to go to insulin", well, I can imagine the conversation, "Oh my God, doctor, I don't really want to do that. Do I have to do insulin? That's really not my preferred treatment choice here." And at least based on the official recommendations, well the way it is now, we're sort of stuck and we might try and have additional conversations, but if the patient prefers not to do it then I think it is very much justified for the provider to buy into that as opposed to, in the past, where the conversation would be, "But, you know, we really need to get this goal. The current guidelines are, we really need to push ahead, I'll help you try and do insulin, and it's really the right thing to do. So that's just my general concern. I think it's a beautiful document -- not a document that you can hand out to the average primary care provider and say, “read this and use all of these guidelines and you're really going to improve care within your practice.”
Dr. Doron Schneider: So thank you for that reflection. Jack, one of the issues that you allude to is delay in intensification of therapy. This is a major problem in primary care, and I wonder if you can reflect on this document and how it handles the need for intensification of therapy and whether it provides the appropriate guidance to clinicians.
Dr. Jack Leahy: So, it continues with the theme of the prior documents and also the general theme in diabetes care to obtain your treatment goal. That's a positive that's buried in there -- that's said in there -- and that should lead to intensification of therapy when needed. On the other hand, what I'm a little worried about is this whole sort of overriding theme - the first thing you read of individualization and patient-centered care opens up the possibility -- I repeat the word possibility -- that people can be a bit slow to advance therapy. If it's not really what the patient is excited to do at this time, it may slow things up, but overall the document continues with effective therapy requires intensification of therapy and moving to additional therapies if needed to obtain a goal.
Dr. Doron Schneider: Great. And as far as that interval for review of goal attainment they recommend a three-month stepwise approach with additional agents added at three-month intervals toward the attainment of goal. Do you believe that that three-month interval is a correct interval to be used for intensification?
Dr. Jack Leahy: Sure, I don't have any problems with that – three months may be too soon, three months may be not soon enough. I mean, I think in retrospect you can go back and look at blood glucose records of patients' and how things are going and feel that things should have been done sooner or faster, but I find that three months is -- if patients are seen three months back, the control is not improving the way it should be--hopefully they've been prepped at that visit that additional decisions will be made if more therapy is needed. So they're ready for that. I'm fine with the three month concept.
Dr. Doron Schneider: One of the clear recommendations is to start with metformin therapy. Can you give us a sense of the clarity of the document regarding patients who present with a high baseline A1C -- say over 9 percent -- and the need to really move patients in a direction of combination therapy or even starting with insulin? Speaking of the primary care doc and the idea of metformin being used initially as a concept that has some traction, does this document do a disservice to the science regarding the ability for metformin to get to goal? Should we be reflecting on the need, or pushing the point a little bit more aggressively, to be more aggressive initially for people with higher A1C?
Dr. Jack Leahy: So this is a very important question and this actually is one of the things I'm not so fond about in this document. One of the big sort of evolutions in the diabetes world over the last 3 or 4 years is an understanding that when we chose initial therapy -- your first drug therapy -- it should be chosen to get the A1C or your treatment goal, let's assume it's A1C, to where you want to get it. That it's not a positive experience in a clinic, quite frankly, if someone comes in, you start a drug and it's not enough because then the conversation after that is, "Oh we need to do something different, you know, you've got to work harder, this is not exactly what I want." It's a much more positive experience to be able to say to patients, "Oh, this therapy's working great. Look at your current values. It's going really well.” I'm happy. They're happy. Okay. So what we know about starting an individual drug -- metformin's a good choice -- but it's not the only choice--- you know, on average those agents will maybe lower an A1C a percent -- some people are more, some people are less -- but about a percent. And so the concept in the endocrine world and the diabetes world has been that if people walk in the door with an initial hemoglobin A1C much above 8.0 percent -- or you can chose your number -- it probably makes more sense to think about starting with combination therapy, i.e., more than one drug. And, in fact, as everybody knows, we have agents on the marketplace now that are two drugs in one pill. And so there is a study that I quote all the time to my house staff (that taking individuals who are treatment naive, who have an average hemoglobin of A1C 8.8 percent), in that study they were given half doses of metformin which was 500 twice a day. If it didn't get you to goal or even close you were then given a full dose metformin of 1,000 twice a day. If [that] didn't get you to goal, give sitagliptin ( whether the DPP-IVs alone didn't get you to goal), but if you had a sitagliptin/metformin combination tablet, especially at the full metformin dose, it absolutely got you to goal. So if you look at the AACE guidelines from the American Association of Clinical Endocrinologists that came out a couple years ago, their guidelines are very much prorated on treatment choices based upon your initial level of hemoglobin A1C. And they say if the A1C is above 7.5 initially you should think about combination therapy. So now we move to the current ADA/EASD position statement. It's a lot more conservative in that regard. It says there are some individuals who may need to start with more than one agent. They talk about a hemoglobin A1C kind of guideline that will point you in that direction as potentially 9 and above. They do talk about that if someone's hemoglobin A1C is reasonably good, certainly less than 7, you can even think about doing lifestyle before moving on to metformin. And it's kind of a step backwards. And so for me this concept of aggressive use of combination therapy at lower levels of hemoglobin A1C than 9 percent, I believe is current, I believe is useful, and I think it's deemphasized in this current document.
Dr. Doron Schneider: I believe we share that opinion. As long as we're talking about patients with elevated A1Cs, I'd like to get your perspective on the patient who's on two agents with an A1C greater than 8.5. And per the position statement there seems to be equal weighting to adding a third oral drug versus moving to that third drug being insulin. And I'm wondering if you can reflect for us on, at least your thoughts ,about the likelihood of success for adding a third oral agent and for someone with still a high A1C of 8.5 and really what is the optimal combination and this document does not provide guidance. It provides equal weighting for both of those options.
Dr. Jack Leahy: So, I think your description is correct. Certainly visually in that figure that's what it looks like. I'm not sure if the authors would necessarily sit down and say that that's exactly what they feel, but certainly that's the way it looks. And the answer to this is really important because this is a common, everyday scenario in so many doctors' offices. If the standard starting drug is metformin, many providers in this country (or really around the world) then use a sulfonylurea for second choice. There used to be TZD usage [but] that's reducing because of problems with that drug, and there certainly is more usage with the DPP-IV inhibitor. But still having said that let's assume a patient comes to you and if they're on the two drugs we'll start with metformin and a sulfonylurea, and if their A1C is 8.5 percent and if the discussion with the patient is, "I would like another pill. Don't give me injection," then your choices are the following: you know, you could do a TZD, an insulin sensitizer. For some people it's magical. For some people it doesn't do much. There is a weight gain potential. It's an expensive drug. And, you know, we're all a little bit nervous about that class of drugs these days in part because of all this discussion about bladder issues, but also the bone fracture risk in woman. So, you know, it's probably not going to get you to goal if you're 8.5 down to -- all the way down to 7 -- and it comes with some significant baggage. So that would be a very limited choice, quite frankly. The other kind of oral agent that people love to talk about are the DPP-IV inhibitors because they're cool and they're new and there's a lot of discussion among the pharmaceutical companies in a lot of CME presentations, and they're just the new drugs on the block, but the problem is that their efficacy in terms of improving hemoglobin A1C is really pretty modest -- as modest as our most modest drugs. And with the hemoglobin A1C of 8.5 where people are on two oral agents if it dropped another one percent when you added to DPP-IV that would be unusual. In most situations it's less than that so now you're going to have people on three oral agents -- one of which, DPP-IV, is really expensive and they're still not going to be to goal and you're going to be having ongoing discussions with your patient about "we need to do something in addition." So the real discussion for me when you're up at 8.5, is you want to choose a therapy that has a real chance -- a very significant chance of that change -- to get someone to goal. And the marketplace war right now is basal insulin, which I happen to love and have used, you know, for years. And I think it's incredibly powerful and comes with not a lot of baggage versus the injected incretin drug -- the GLP-1 receptor agonist --and there are many, many head-to-head trials suggesting that at that chosen level of hemoglobin A1C of 8.5 percent both of those have a very significant chance of getting someone to goal, and they come with different clinical profiles. We all know the profile of insulin and the profile of the GLP-1 drugs: positive is maybe some weight loss and some improvement in cardiovascular risk factors; negative([s] [are] cost [and] some GI side effects. So that to me would be the classic part of the document, which is to sit down with the patient and say, "Well you know the best choice, in that situation, is insulin versus GLP-1. Let's talk about those two drugs, and then let's make a decision of what you want to do".
Dr. Doron Schneider: I think you're comments reflect very much what's going on in the primary care world. However, I think that the first half of your comments were [that] the patient not wanting to go to an injectable occurs more often than not. There is an injection barrier. These statements -- this position document, by visually[representing] in the figure, which is to your point, the thing that does get the most traction in reproduced versions of this,(talks in the media, etc.) by providing equal weighting in this document visually without the context of the likelihood to get to goal is an enabler in a way for the primary care community to add a third oral agent as opposed to moving to a more efficacious option, to your point, that will get patients to goal. And so, I'm a little concerned, and I think we're on the same page about this.
Dr. Jack Leahy: So, I just want to deal with the issue you said of the patients not wanting to do an injectable. That's of course true. And one of the things that interests me is I'll have conversations with our local primary doctors, and they'll tell me how that's an incredible barrier to intensifying therapy in their practice, and I understand that. But having said that, no one comes to my clinic who really wants to start injectables. It's not their favorite thing and so it very much becomes the conversation of balancing pluses and minuses. And showing patients that the injection is not a big deal. So one of the things that fascinates me is I was recently in a meeting where someone showed data that about 95 percent of primary care doctors identify pain and/or discomfort from the injection as being a major barrier in starting injectables. That's what patients felt and that was a big issue. But then when you look at what percentage of those doctors were actually having patients injected with a needle during the office visit, it's very small. And that to me is a total disconnect because as soon as someone is given a needle injection or can look at the needles or look at the pens and see how incredibly small and relatively easy the system is, it really diffuses a lot of the fear. So I understand the barrier, but I think what needs to be introduced in someone's practice are countermeasures against that barrier and it becomes less of a problem.
Dr. Doron Schneider: I completely concur. This document does tread lightly in the guidance regarding implementation of injection therapy. It does not really speak to it in how to really be patient-centered in the approach to allowing patients the benefits of more efficacious drugs such as insulin and perhaps the GLP-1s. So that might be a short-coming that needs to be really looked at. As long as we're on the concept of providing drugs that are efficacious to patients to achieve goal, I wonder if you can give us your thoughts about the drugs that don't appear on this guideline or position statement at any level. There are some entire classes that are omitted, and the authors indicate they are omitted because [of] their modest efficacy and mitigating side effects. And I wonder if you have any thoughts on those other classes.
Dr. Jack Leahy: Well, one notable exception is the alpha glucosidase inhibitors or the drugs that essentially slow the absorption of carbohydrate. You know, in this country I don't think many providers are going to be surprised by that because it's a very unusual practice that uses much of that. I will say in other parts of the world -- and I want to reinforce that this position statement is read by the whole world --they may be recommendations that are specifically under the banner of the Americans and the Europeans, but they are clearly used and thought about internationally and when you go to Asia and other parts of the world, the alpha glucosidase inhibitors continue to be actively used. I don't have any strong feelings really either way. I think [in] the areas of the world they're used, people have a pretty good idea when they work and when they don't work. That's the same concept of treatment inertia so you can use one of those drugs --" it works for me, but if it's not effective you then need to move onto additional therapy". There are some newer agents -- there's bromocriptine, for instance, so that's probably another somewhat omission from this, if you want. So if they wanted to be complete you could say bromocriptine. I think the average provider, most endocrinologists, and certainly the average primary care doctor has no experience with that agent in the treatment of Type 2 diabetes. And it's okay. It has some improvement in cardiovascular risk factors. It has a modest lowering of hemoglobin A1C. It's not a major agent used, and I probably am not unhappy that it's been omitted.
Dr. Doron Schneider: Thank you. This idea of medications that may not be as efficacious, but not being on this position statement, certainly makes intellectual sense to me. There are medications that simply do appear on these guidelines that may not work for individual patients. Patients may be a non-responder, if you will, to the medications that do appear on the guideline. Often what I see in primary care is, rather than reflecting on the lack of response, we continue to move to add additional therapy, thus increasing complexity, costs, side effects, etc. And I wonder if you have an approach to looking at withdrawing medications that may not be working for folks in providing any wisdom to the primary care community regarding this concept of non-responding. And then a second follow-up question is really the fact that when you're a non-responder the other part of the differential diagnosis is that you may not be adhering to the medication and not taking it and if you don't really adhere, you're not going to respond. So any words of wisdom of how you deal with folks whose A1C just is not moving, their blood sugar and self-monitoring data suggests that it is not efficacious, and how you handle that situation?
Dr. Jack Leahy: So this is a spectacular question, and I think you should really look at the diabetes specialty community. One of the really active conversations now that's growing is as people look at studies of insulin therapy, of GLP-1 drugs, of really any of the traditional oral agents, you will find sub groups of people. Some people respond very well to that therapy, and other people don't respond well to that therapy -- just as true for insulin as it is for these other agents. There's a lot of confusion out there and questioning, well is there a biology, or are there some other underlying issues that we could identify and figure out what's the best therapy? We're not there yet, but that's clearly an interest and may be fruitful for the future. So in terms of your question, actually it's something I don't routinely have a clear sort of guideline in my practice what I do. You have to realize that I'm a referral endocrinologist. The people are sent to me, by definition, typically are on multiple diabetes agents and failing. And more and more people are sent to me on insulin programs and multi-shot insulin programs along with other agents and failing. So part of my discussion with them is to try to understand why, and certainly part of the reason why is because people don't take the medicine the way they're prescribed or even sometimes the way the primary care doctor thinks they do. Certainly, a huge part of the conversation with me for people who are on insulin programs that seemingly are reasonably good doses and reasonably good programs, but still A1Cs are 9, 10, 11, I do a lot of discussion with people about (-- I have this little game I play --) "over a seven-day week, how many injections of glargine lantus might you forget to take?" as opposed to an open-ended question, such as "do you really take your insulin?" kind of thing. Then I try and map out what they're taking. Sometimes they're people who are not taking their medicine, and then we have long discussions about that to find an adjustment. But also there are people who are on medicines where they just don't seem to work for them. And then it becomes an individual choice as to whether it's taken away or not. I think it's almost like blood pressure where we don't often take drugs away. We stack drugs on top of each other. So if someone comes to see me and if they're on say, three oral agents, and I'm adding basal insulin, I don't often take things away. I mean if they're on metformin, I like it with basal insulin. If they're on a sulfonylurea well they'll probably stay on it until we see if the basal insulin is going to work for them. The agent of discussion would be the TZD, and that's mostly because we're afraid of those drugs and in combination with insulin maybe there's going to be more weight gain or some edema. You know, maybe that's one agent I might think of taking away, but it's hard to do it. If someone's on these three drugs and their A1C is 9, you take one away and you think, "oh my God, it's going to get worse." So I'm a little embarrassed to say I do not have any formal system that when I'm adding an agent I necessarily [take] away agents that I think may be ineffective. I think that's just sort of evolved for different patients and how it happens to evolve.
Dr. Doron Schneider: You're really describing the art of medicine -- there is not a lot of guidance out in the world -- scientific guidance -- for that issue of the non-responder and how to optimally deal with that. The issue of addressing non-adherence is a critical one. There are multiple data sets that suggest that for these medications that are being used to treat chronic illness that don't have symptoms -- high blood pressure, being a great example, that the rate of adherence is extremely low -- osteoporosis drugs, etc. And we need to be aware of that and have that very high in our differential diagnosis of the non-responder and develop systems of care to screen for patients as they present for routine office visits for non-adherence. I do like your approach which is one that normalizes that for patients, that recognizes that they are human and may have omitted doses and asking them in a nonjudgmental way, as you do, is a very reasonable strategy that we need to be thinking through as we develop more robust systems in the primary care world. Non-adherence is a very critical problem.
Dr. Jack Leahy: You know, just sort of one comment related to that -- specialists in particular live in this world of thinking about their own illness. So, you come to see me and I'm thinking about your one or two or three diabetes agents and how I'm going to adjust things. Primary care doctors live in a world where these patients are on lipid drugs and blood pressure drugs and drugs because their joints are hurting and they're depressed and, you know, you look at these long lists of medicines -- people on 8, 10, 12, 15 agents and then, you know, who can do that? I think if you saw a patient who took all of their medicine absolutely in a bulletproof way, you'd be amazed and a bit skeptical. So this multiple medicine and non-compliance is really an extraordinarily complicated issue.
Dr. Doron Schneider: Right, and one that we have yet to solve. Coming back to the guidelines, I wonder if you can give us your thoughts or reflections on beta cell preservation. As it stands in the guidelines, the authors do speak to the fact that insulin -- I'm sorry-- that there's multiple defects that are occurring, beta cell resistance and beta cell failure -- and states that is a reality and our current state of the science in that we just don't know necessarily in humans especially how these drugs may or may not preserve beta cells, you know, over long periods of time, and they don't position beta cell preservation in any algorithmic way or in any guidance. And I wonder if you can reflect on that, and how should the primary care world be thinking about making a selection of agents based on beta cell preservation as a factor at all?
Dr. Jack Leahy: So this is a great question, and in some respects I'm probably more in line with the authors of the document on this issue than maybe some of the other issues. I don't think we know enough in today's world to be making treatment choices based upon presumptions of how individual drugs may alter the natural history of the disease versus other drugs. Certainly we can go back five or eight years ago. One of the disappointing, I think, eye openers in our world from the UKPDS and some of the later studies was a recognition that you can start any of our therapies that start out being reasonably effective, and with time their effectiveness wanes, and that seems to correlate in part with worsening beta cell function and certainly there is a lot of discussion and a lot of hope that we will identify ways -- be they through specific agents or through some other mechanism -- to change the loss of beta cell function, and therefore, change response to drugs and the natural history of the disease. So the real issue is do we have any of that with any individual drugs, and should that be built into the guidelines, and I think probably the short answer is probably not. There was hope that the insulin sensitizers would do some of that, and I would say if you look at the data on insulin sensitizers in a reasonably fair, balanced way, they may do better in terms of changing the natural history of the disease than some of our even prior agents to that of metformin and sulfonylurea. How long that lasts I'm not exactly sure and again we're a little bit afraid of those drugs and so that's probably not our future. So the other agents that we've thought a lot about are the incretin agents and the oral agents, the DPP-IV inhibitors and the injected drugs -- the GLP-1 drugs. And there was just enormous excitement that they might actually improve beta cell biology in this disease and bring this goal of beta cell protection that's based a lot on both of these agents having been used in rodent models with Type 2 diabetes and in both of them they acted to build the beta cell mass -- something that would be spectacularly useful if it had occurred in humans. And so we all waited with semi-bated breath to see if it looks like that occurred and we don't have full information yet, but I think prevailing opinion is probably not. So, when we look at those agents now when you take one of the drugs especially the injected drug GLP-1 drug, they seem to improve beta cell function over the long term. So if you're on the agent it looks even maybe four years out, beta cell function looks pretty good. So from a beta cell protection point of view it may turn out that they are more effective at improving beta cell function over the long term and then having a longer duration of action in terms of efficacy than our traditional agents. But we don't know that yet and, therefore, it's really premature to try and build that into a guideline. Now the last part of this conversation, and the one that's timely, is well, could insulin actually, if used early and used aggressively, change beta cell function and be protective. There's some information going back a few years that suggests that maybe and, in particular, a very exciting study that was done in China a few years ago used insulin as an initial therapy very aggressively and then stopped it and, in fact, people went into remission in the disease -- for more than a year in some people. And then we have the ORIGIN trial which was reported on just a month or two ago at the American Diabetes Association, which is using glargine Lantus insulin very early in the course of Type 2 diabetes -- even in some patients in pre-diabetes -- and one of the findings of that study was the concept that people moving from pre-diabetes to actually Type 2 diabetes seem to be protected better by an insulin injection as opposed to an oral agent like metformin. It was a fairly minor difference, but it was real. So, maybe insulin has a modest effect for beta cell protection, but when you put all this together I don't think any of this is so secure that this particular feature should be driving our treatment choices and be a prominent part of any treatment outlook.
Dr. Doron Schneider: Okay and just for clarity's sake, the idea of the incretins -- you refer to their durability of action, their possible preservation of function over the long haul -- would you suggest that to take fullest advantage of that durability that there's any benefit to beginning incretins earlier in light of your insulin comment? Should that be how we think about incretins in general?
Dr. Jack Leahy: I don't think we know yet, but it is a really, really important question. There's a fascinating study from the United Kingdom that was published a few years ago of using liraglutide (Victoza) in patients with pre-diabetes, and they happen to use a very large dose -- a dose that's more than what's clinically-approved right now. And they looked at weight reduction as one of the dominant clinical outcomes, and it showed that this very high dose of Victoza -- 3 milligrams a day -- there was just an enormous weight reduction over about 20 weeks of the study, but also the pre-diabetes basically disappeared. There was about a 90 percent reversal of pre-diabetes to normal glycemia. You might expect that because these people lost a lot of weight. So I don't think we know, but certainly one of the big discussions in the diabetes speciality world right now is we're interested in these GLP-1 drugs, and we're trying to figure out when best to use them and what clinical benefits will come with long-term usage of these drugs, and that's still very much an open issue.
Dr. Doron Schneider: Thank you. Jack, I want to return back to the guidelines, and one of the very first things that needs to occur over the management of patients with diabetes is goal setting. And this guideline or position statement does really for the first time clearly articulate that we need to be patient centered in that goal setting. They very clearly and in graphical form do bring out the patient characteristics that should lead to either more stringent or less stringent goal setting. And those characteristics include patient attitudes and expected treatment efforts: the risks associated with hypoglycemia; the duration, life expectancy, important comorbidity, established vascular complications; and finally resources and support system. And that is -- those represent some of the variables that need to be weighted in goal setting. And I wonder if it may be an evolving role of the endocrinologist in their relationship with the primary care doctor is to help establish the goals of care. Does this belong at a primary care level? Does it belong at the endocrine level? This is a very critical thing for us to get right as we need to ensure that that balance of safety does occur against the expectance and the possible benefits of driving people down. Who should be driven down to a goal of A1C of even 6.5? This does require a certain level of expertise that I worry does not currently exist in the primary care community and that is a major departure in this position statement, and I wonder if you have any reflections on this notion of goal setting.
Dr. Jack Leahy: So this is a hard question because it is very much a moving target. I'm in total agreement. It makes a hundred percent sense to me that if the only criteria that's used to define success or failure with a diabetes drug is attaining a certain level of blood glucose control and/or level of hemoglobin A1C, that is limited and a bit naïve, and this concept of individualization of care should be done. So, I'm a total believer in this concept of individualization of care, and I just don't think that there is a primary care doctor who sees patients who thinks that the idea of basing all the decisions that success or failure is based upon blood glucose control and level of hemoglobin A1C and nothing else is complete, and I totally agree with that. But what factors are most important factors is how you weight those is incredibly complicated and incredibly difficult, and I think a comment maybe for this, really, is the art of medicine. That the discussion with any individual patient -- what are the dominant issues for them, what is most influential for them, and what is going to be most beneficial in their overall healthcare, is where we should all shoot for. Now, now, the sort of the one easy part of this discussion -- or at least one direct part of this discussion -- is having said all of that, what we do with blood glucose goals because that has been a very confusing issue in the last couple of years related to the ACCORD trial and to the ADVANCED study and to the Veterans study and ORIGIN, and what do we actually do in terms of the blood glucose goals, and I think a reasonable summary to take away from all of that would be to say that early intensive blood glucose control, when the disease is fairly new and when patients are fairly healthy and when there's not any other major overriding illnesses getting in the way, makes absolute sense and a hemoglobin A1C of even less than 6.5 very early in the course of the disease seems to bring long-term benefits. Going to the other end of the spectrum when there's a lot of other comorbidity and a lot of other disease, especially cardiac disease and people are failing, or at least not intensively treated already on a couple of diabetes agents, I think one can buy into being a little bit conservative and not be nearly as intensive and going slowly and having a development of goals, avoidance of hypoglycemia because I think we're a little afraid of that and certainly in those kinds of patients. And then for the huge group of patients in the middle that the average primary care doctor sees who are not that sick or have the disease for a while, they're failing an agent or two, but they're, you know, they're not that old, I think the goal of less than 7 may make absolute sense, is defendable, and seems to bring some benefits.
Dr. Doron Schneider: Thank you for your wisdom. And reflecting back on other conditions that this type of crisp clarity may exist at least in guidelines and in thinking about the measurement of cholesterol, for example, and the tack that has been taken by thought-leaders and guidelines to provide guidance off of the Framingham calculator for cardiovascular risk is where we need to heading, I believe, for the guidance required for the primary care community to be able to put in factors into a calculator to say this should be this patient's goal. And that may be the evolution of how we do goal setting as the stakes are going to increasingly be raised. We're entering an environment now that looks at score carding physicians, that looks at that score carding being transparent and available to the public, and the control of diabetes is a prominent feature of score cards. And being able to administratively look at a database and exclude patients who should not be at goal, less than 7, for example, becomes increasingly important as that information is used for the migration of healthcare to become consumer driven, for patients to begin the process of selecting their clinicians, their doctors, based on outcomes, and then even more so payment models are beginning to evolve to reward physicians toward the attainment of goal. These are sort of the next steps for us to be really thinking about from a policy perspective, from a payment perspective and will really need to be addressed in future iterations of guidelines, consensus data, and position documents. So initial reflections regarding the primary care community include the fact that diabetes clearly is a team sport. That team needs to reflect the patients and to empower patients to be able to manage their conditions optimally as they're spending their life not in the doctor's office. They need to have self-management techniques and skills and knowledge, and the rest of the team needs to be really defined at each primary care office. Who is your resource from a diabetes education stand point? How are you using the other members of the office staff that you have to deliver good primary care for diabetes? The model that we like speaking to is the chronic care model and that really does look at patients and their self-management, redesign of office systems, using clinical decision support at the bedside, using information systems to their utmost, and when primary care offices really are utilizing all four of those and really running on all cylinders the likelihood of positive outcomes really is increased. This position statement did not provide necessarily a level of guidance that is operational to allow people to take this and use it at the bedside, but one of the next steps that needs to occur to provide tools that can be used by nurse practitioners, physician assistants, these extenders that are increasingly being used as frontline diabetes managers within teams that are led by physicians. That translation table, if you will, needs to be built and needs to be easy to use by folks who are doing the vast majority of care. So, I look forward to seeing what is created by those that are consuming this position statement because that is the next step -- the translation from position statement to tools at the bedside -- that is needed.
So having said that I'd like to thank Dr. Jack Leahy for his reflections on this recent ADA/EASD position statement. We had a wide-ranging conversation that really touched on all facets of the statement. We look forward to the feedback of the readers and the listeners of Beta Cells in Diabetes and we would like to hear your comments, suggestions, thoughts and reflections on what you've heard and please submit them to us here or  email to contact@betacellsanddiabtes.org. Thank you.