Combination Therapies and Intensification of Therapy


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 current 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. 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 it’s 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. It really does require these primary care docs to understand the nuances of those trials.
Dr. Jack Leahy: Great, Doron, right on target. So we have this new set of guidelines. You know they're called a position statement from the ADA/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 different agents that are out there and also tries to build in a philosophy as to how providers should approach this. And probably the first thing you read is this concept of individualization of care. This idea that an A1C of 7 is right for everybody is really gone, and now it's focused on identifying 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. And then it moves into specific recommendations of the kinds of therapies that are out there and how they might be used. There's general agreement that the appropriate starting drug in Type 2 diabetes for most patients is metformin. 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. 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.
Dr. Doron Schneider: Are there features of this position statement that is worrisome to you?
Dr. Jack Leahy: 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 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. Secondly, it worries me and I worry a lot about the concept of just people stuck and not advancing therapy. Because at least in the prior guidelines, or the prior consensus statements, there was a real push 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.
Dr. Doron Schneider: 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 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 not be 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 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 they 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 permissions in a direction of combination therapy or even starting with insulin? Speaking as a primary care doc seeing 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, and 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 conversations 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 A1C a percent—some people are more, some people are less—but about a percent. And so the concept in the endocrine world or 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 who are taking individuals who are treatment naive, who have a 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 given a full dose metformin of 1,000 twice a day didn't get you to goal, give sitagliptin or one of 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 ACE 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. It's kind of a step backwards. And so for me this concept of aggressive use of combination therapy at lower levels of hemoglobin level of 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. So, having said that I'd like to thank Dr. Jack Leahy for his reflections on this recent ADA/EASD position statement. We look forward to the feedback of the readers and the listeners of Beta Cells in Diabetes. We'd like to hear you comments, suggestions, thoughts and reflections on what you've heard. Please submit those at betacellsanddiabetes.org. Thank you.